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Inflammopharmacol DOI 10.1007/s10787-010-0073-1

Inammopharmacology

REVIEW

REVIEW

Lysyl oxidase: a potential target for cancer therapy

Siddikuzzaman V. M. Berlin Grace C. Guruvayoorappan

Received: 3 September 2010 / Accepted: 2 November 2010 Springer Basel AG 2010

Abstract Lysyl oxidases (LysOX; EC 1.4.3.13, protein- lysine 6-oxidases) are extracellular copper enzymes that catalyze the cross-linking of collagens or elastin in the extracellular matrix (ECM), thereby regulating the tensile strength of tissues. Recent implication of LysOX in cancer, wound healing, cell motility, chemotaxis, and differentia- tion reflects its remarkable functional diversity and also in the central nervous system pathologies. However, recent reports also demonstrated novel roles for LysOX, including the ability to regulate gene transcription, motility/migra- tion, and cell adhesion. These diverse functions have led researchers to hypothesize that LysOX may have multiple roles affecting both extra- and intracellular cell function(s). Both down and up-regulation of LysOX in tumor tissues and cancer cell lines have been described, suggesting a dual role for LysOX as a tumor suppressor, as well as a metastasis promoter gene. In this review we explain in detail the role of lysyl oxidase in tumor progression and metastasis.

Keywords

cellular matrix Cancer Tumor suppressor

Metastasis promoter

Lysyl oxidase Copper Extra

Introduction

The extracellular matrix (ECM) is essential for providing mechanical and physiological properties for various tissues, and it also provides attachment sites for the anchoring of

Siddikuzzaman V. M. B. Grace C. Guruvayoorappan (& ) Department of Biotechnology, Karunya University, Karunya Nagar, Coimbatore 641114, Tamil Nadu, India e-mail: gurukarunya@gmail.com

641114, Tamil Nadu, India e-mail: gurukarunya@gmail.com cells and support for their migration in tissues. It also

cells and support for their migration in tissues. It also sup- ports physical structure formation of tissues during development and tissue maintenance, determines cell– matrix and cell–cell interactions, and provides a structural and signaling environment that is necessary for cell migration, proliferation, and differentiation. The ECM plays a pivotal role in regulation of cellular functions during embryonic development, tissue repair, inflammation, tumor invasion, and metastasis (Hynes 2002; Juliano 2002). The composition of the ECM is unique for each organ. It con- sists of numerous compounds including insoluble fibers, microfibrils, soluble proteins, and glycoproteins. The lysine residues of the ECM molecules, such as of collagen and elastin go through oxidative deamination by the extracellular enzyme lysyl oxidase (LysOX), a copper dependent amine oxidase, which forms reactive aldehyde of its substrates (Kagan 1994; Gibson et al. 1996). The newly formed aldehyde residues then interact spontane- ously to form covalent cross-linkages leading to insoluble extracellular protein matrices in most tissues and organs (Nagan and Kagan 1994; Smith-Mungo and Kagan 1998). The essential function of LysOX in the ECM and LysOX cellular distribution in the skin, lung, and the cardiovas- cular systems have been well characterized. Recently, in addition to its ECM cross-linking activity several studies reported novel roles for LysOX in diverse tumor types and a major role in invasive breast cancer cells and tumors. Although the ECM maturation activity of LysOX has long been thought to be its sole function, more recent evidence implicates the involvement of LysOX in many critical biological functions other than collagen or elastin cross-linking. LysOX has been shown to induce motility and migration in monocytes, vascular smooth muscle cells, and fibroblasts (Nelson et al. 1988; Lazarus et al. 1994; Li et al. 2000). In addition, LysOX expression and activity

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have been observed in the cytoplasm and nucleus (Waka- saki and Ooshima 1990; Li et al. 1997; Nellaiappan et al. 2000; Kagan and Li 2003; Lucero and Kagan 2006; Jansen and Csiszar 2007) and implicated in cell signaling and transcriptional gene regulation, as evidenced by utilization of histone H1 and H2 as substrates (Kagan et al. 1983; Giampuzzi et al. 2003a), altered chromatin condensation (Mello et al. 1995), activation of the collagen III a1 pro- moter through LysOX induced binding of Ku antigen (Giampuzzi et al. 2000), inactivation of the transcription factor NF-jB (Jeay et al. 2003), and regulation of cell adhesion through increased b-catenin and cyclin D1 expression (Giampuzzi et al. 2005). Even more recent are the findings that LysOX protein domains, other than the catalytic domain, can bind to proteins, as with binding to fibronectin (Fogelgren et al. 2005) and placental lactogen (Polgar et al. 2007) and that the cleaved 18 kDa LysOX propeptide (LysOX-PP) is also capable of regulating bio- logical functions (Palamakumbura et al. 2004). Since LysOX protein structure and function are so complex and involve such vital biological processes as cell movement, signal transduction, and gene regulation, it is evident that aberrant regulation of LysOX would lead to tumorigenesis and tumor progression. Indeed, loss of LysOX expression and activity in a number of cancers and oncogene-trans- formed cell models has implicated LysOX as a tumor suppressor gene. Likewise, LysOX expression and activity in a number of cancers has also been observed and has implicated LysOX as a metastasis promoting gene—cre- ating a conundrum within the LysOX research field with regard to LysOX biological function(s) in cancer. This review will summarize the role of LysOX in tumorigenesis and tumor progression with an emphasis on cancer meta- static progression.

The lysyl oxidase protein family

Lysyl oxidase (LysOX; protein-6-oxidase [EC 1.4.3.13]) is the key enzyme that controls collagen and elastin matura- tion (Pinnell and Martin 1968; Smith-Mungo and Kagan 1998). LysOX is the copper- and quinone-containing amine oxidase that catalyzes the oxidative deamination of peptidyl lysine in elastin and collagen to a-aminoadipic-d-semial- dehyde, the first step in formation of the cross-links that stabilize these structural proteins (Faina and Frederick 2010).The consequent aldehydes lead to a spontaneous condensation forming inter- and intrachain cross-links. This posttranslational modification of ECM molecules plays a very important role in collagen and elastin structural aspects and possibly in triggering still-unknown signal transduction pathways. Several reports have suggested a clear associa- tion between organ fibrosis and increased LysOX activity

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(Chanoki et al. 1995; Jourdan-Le Saux et al. 1994; Sommer et al. 1993). The most intriguing aspect regarding LysOX activity relates to its putative cell phenotype control and tumor suppressor activity. LysOX was identified as a ‘‘ras recision gene’’ (rrg), and levels of LysOX were found to be decreased in cells transformed by ras or ras-dependent oncogenes (Contente et al. 1990; Kenyon et al. 1991; Krzyzosiak et al. 1992). Furthermore, Friedman and coworkers showed that ras-transfected NIH 3T3 cells induced to revert by beta or gamma interferon would return to their transformed phenotype upon transfection with an antisense LysOX vector, and retransformation did not affect p21 ras levels (Contente et al. 1990; Kenyon et al. 1991). In many naturally occurring and oncogene-induced tumors, LysOX is down regulated, and LysOX was induced con- comitantly with reversion (Contente et al. 1990; Kenyon et al. 1991; Krzyzosiak et al. 1992; Giampuzzi et al. 2001; Hajnal et al. 1993; Ha¨ma¨la¨inen et al. 1995). However, this oxidative activity does not display high specificity because LysOX can also oxidize additional lysine-rich proteins such as histone-H1, as well as various lysine-rich synthetic peptides (Kagan et al. 1983; Ohkawa et al. 2001). It was observed that LysOX can be translo- cated into cell nuclei and that it can regulate, by an as yet poorly understood mechanism, the expression of collagen- 3A1, indicating that LysOXs may have additional functions (Nellaiappan et al. 2000; Giampuzzi et al. 2000). LysOX is synthesized as an inactive proenzyme that is activated by the products of the BMP-1 gene (Panchenko et al. 1996). Recently, several additional LysOX family members were identified. These new family members are characterized by the presence of a conserved LysOX-like domain containing conserved copper binding and catalytic domains at their COOH termini. These new LysOXL genes include Lys- OXL (Kenyon et al. 1993; Kim et al. 1995), LysOXR-1 or LysOXL2 (Saito et al. 1997), LysOXR-2 or LysOXL3 (Huang et al. 2001), and LysOXC or LysOXL4 (Maki et al. 2001). LysOXR-1, LysOXR-2, and LysOXC differ with respect to LysOX and LysOXL in that they possess a much longer NH2-terminal domain, suggesting that they consti- tute a distinct subclass of LysOXs and that their functions may differ fundamentally from those of LysOXL and LysOX (Csiszar 2001). LysOXR-1 was initially identified as a gene the expression of which is up-regulated in senescent fibroblasts and in adherent tumor-derived cells (Saito et al. 1997). It was also found to be highly expressed in reproductive tissues (Jourdan-Le Saux et al. 1999). It was demonstrated that LysOXL is also processed into its active form by bone morphogenetic protein-1, raising the possibility that the proteins encoded by the other family members may also be activated by proteolytic digestion after secretion. The transition from a localized tumor to an invasive and metastatic tumor represents a landmark in the

Lysyl oxidase: a potential target for cancer therapy

development of malignant disease because it is usually associated with a markedly worse prognosis. The under- standing of the processes that govern this transition is therefore, of prime importance. It was recently observed that, in breast cancer the transition from a localized to an invasive/metastatic tumor is associated in many cases with the formation of fibrotic foci and desmoplasia (the presence of unusually dense collagenous stroma) within the primary tumor (Colpaert et al. 2001; Hasebe et al. 2000). There are also some indications that a similar correlation may exist in other types of cancers such as in colon cancer and in pancreatic cancer (Nishimura et al. 1998; Ellenrieder et al. 2000). These observations represent apparent paradoxes at first glance because invasiveness has long been associated with the destruction of ECM by ECM-degrading enzymes like metalloproteases (Stamenkovic 2000; Duffy et al. 2000) and heparanase (Vlodavsky and Friedmann 2001). However, it is possible that the deposition of excess ECM may stimulate, in turn, expression of matrix-degrading enzymes that will contribute under certain circumstances to tumor invasion. In fact, there is some evidence that an increase in ECM deposition can, indeed, influence the production of ECM-degrading enzymes (Schuppan et al. 2001; Sawada et al. 2001). Two LysOX family members, LysOX and LysOXL, were found to be expressed in areas of fibrogenesis in noninvasive in situ ductal breast carci- nomas (Decitre et al. 1998). However, it was reported that metastatic breast cancer cell lines express LysOX, Lys- OXL, and LysOXR-1, whereas nonmetastatic breast cancer-derived cell lines, such as MCF-7 cells, do not, and that LysOX-expressing MCF-7 cells display increased invasiveness in in vitro invasiveness assays (Kirschmann et al. 2002). It also reported that LysOXR-1 expression in nonmetastatic MCF-7 cells induces massive deposition of dense collagen fibers and the formation of numerous fibrotic foci in tumors that develop after the implantation of these cells in nude mice. These changes were accompanied by an increase in the invasiveness of the MCF-7 cells, although the LysOXR-1-expressing cells were still estro- gen dependent.

Physical and biological properties of LysOX

LysOX is a copper-dependent amine oxidase that initiates the covalent cross-linking of collagens and elastin in extracellular matrices (Smith-Mungo and Kagan 1998; Csiszar 2001). It is secreted as a M r 50,000 glycosylated proenzyme, which is proteolytically processed by procol- lagen C proteinase (bone morphogenic protein-1) into a mature, biologically active M r 32,000 form (Smith-Mungo and Kagan 1998; Csiszar 2001). The formation of collagen/ elastin cross-links by LysOX leads to an increase in tensile

strength and structural integrity and is essential for normal connective tissue function, embryonic development, and wound healing (Smith-Mungo and Kagan 1998; Casey and MacDonald 1997). Consequently, aberrant LysOX expression or enzymatic activity leads to disease. Decrea- ses in LysOX expression or activity have been associated with such heritable connective tissue disorders as Ehler- Danlos syndrome, cutis laxa, and Menkes’ syndrome (Kuivaniemi et al. 1985; Khakoo et al. 1997; Yeowell et al. 1994; Royce et al. 1980; Pinnell 1982). Increases in LysOX expression contribute to the development of fibrotic dis- eases such as arteriosclerosis, scleroderma, and liver cirrhosis, diseases that involve connective tissue remodel- ing (Ooshima and Midorikawa 1977; Kagan et al. 1981; Chanoki et al. 1995; Kagan 1994). Upregulation of lysyl oxidase expression by uric acid leads to increases fibro- nectin synthesis in rat renal tubular epithelial cells (Zhou et al. 2010). Although the ECM maturation activity of LysOX has long been thought to be its sole function, more recent evidence implicates the involvement of LysOX in many important biological functions other than collagen/elastin cross-linking. LysOX has been shown to induce motility and migration in monocytes, vascular smooth muscle cells, and fibroblasts (Lazarus et al. 1994; Li et al. 2000; Nelson

et al. 1988). In addition, LysOX may play a role in cell

growth/differentiation as its expression is up-regulated by a number of growth factors and steroids (Lazarus et al. 1994;

Li et al. 2000; Nelson et al. 1988; Sanada et al. 1978).

Moreover, a role for LysOX in transcriptional gene regu-

lation and cellular transformation has also been implicated

as evidenced by localization of LysOX protein and enzy-

matic activity to cell nuclei (Li et al. 1997), potential utilization of histone H1 as a substrate (Kagan et al. 1983), activation of the collagen III a1 promoter (Giampuzzi et al. 2000), and a putative tumor suppressor in nontumorigenic revertants of ras-transformed fibroblasts (Smith-Mungo and Kagan 1998). LysOX was purified from a variety of tissues and spe-

cies including chick cartilage, bovine aorta and lung, human placenta, and piglet skin (Stassen 1976; Kuivaniemi

et al. 1984; Cronlund and Kagan 1986; Shackleton and

Hulmes 1990). The molecular mass of the enzyme from all these sources was found to be 30 kDa (Panchenko et al.

1996; Kagan and Li 2003). LysOX has been cloned from

rat (Trackman et al. 1990, 1991), human (Hamalainen et al.

1991, 1993; Mariani et al. 1992), chick (Wu et al. 1992), and mouse (Contente et al. 1993) tissues. The mRNA for human LysOX is found as multiple species with sizes of 5.5, 4.3, 2.4, and 2.0 kilobases due to the use of alternate polyadenylation sites and partially to the existence of multiple transcription initiation sites (Mariani et al. 1992; Boyd et al. 1995). The human LysOX gene is located on

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chromosome 5q23.5–31.2 (Hamalainen et al. 1991, 1993; Mariani et al. 1992; Wu et al. 1992; Contente et al. 1993; Boyd et al. 1995) and encodes a 417 amino acid poly- peptide, of which the first 21 residues correspond to the signal peptide (Hamalainen et al. 1991; Mariani et al. 1992). The mouse LysOX gene has been mapped to chromosome 18 (Contente et al. 1993; Boyd et al. 1995; Mock et al. 1992; Chang et al. 1993).

Substrate and activity of LysOX

LysOX is a copper-dependent secreted amine oxidase that oxidatively deaminates specific peptidyl lysine and hydroxylysine residues of collagen and lysine in elastin in the presence of molecular oxygen (Kagan 1986; Pinnell and Martin 1968; Bateman et al. 1986; Reiser et al. 1992). LysOX can oxidize non-ECM lysine rich proteins such as histone-H1 as well as various lysine-rich synthetic peptides including basic fibroblast growth factor (bFGF) (Kagan et al. 1983; Giampuzzi et al. 2003a; Li et al. 2003). As a byproduct of the catalytic reaction, reactive aldehydes and hydrogen peroxide are generated by the LysOX that may contribute to some of the novel roles of LysOX observed in the wound healing, cell migration, motility, proliferation, and differentiation (Li et al. 2000, 2003; Fushida-Takem- ura et al. 1996; Nelson et al. 1988; Palamakumbura et al.

2004).

The resulting peptidyl aldehydes condense spontane- ously to form various bi-,tri-,and tetrafunctional intra- and inter molecular cross links (Kagan et al. 1984; Siegel 1974). In collagens, the lysine and hydroxylysine-derived cross-links are essential for providing the tensile strength and mechanical stability of the collagen fibrils and other supramolecular assemblies (Light and Bailey 1980; Bailey 2001) (Fig. 1). Collagen are the most abundant proteins in mammals, with at least 35 members divided into 9 families. This multigen family disperses gene throughout 15 or more chromosomes. Collagen molecules consist of three peptide

chromosomes. Collagen molecules consist of three peptide Fig. 1 The catalytic activity of LysOX: LysOX oxidatively

Fig. 1 The catalytic activity of LysOX: LysOX oxidatively deami- nates a peptidyl lysine to generate a peptidyl allysine which spontaneously reacts with another peptidyl lysine or allysine to form a covalent cross-link between proteins (Kagan 1986; Kagan and Cai

1995)

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chains called a chains, and contain at least one triple- helical collagenous domain with repeating (Gly-X–Y) n sequences, i.e., a glycine residue as every third amino acid, with the frequent presence of proline and 4-hydroxyproline in the X and Y positions, respectively. After post-transla- tion modification in the extracellular space, the precursor of fibrillar collagen, called procollagen, undergoes prote- olytic conversion to form collagen molecules. Collagen molecules form fibrils and interact with non-collagenous and collagenous protein, while they assemble into supra- molecule structure where the fibrils are stabilized by the formation of intra- and intermolecular cross-links (Byers 2001; Myllyharju and Kivirikko 2001; Koch et al. 2001; Fitzgerald et al. 2001). Elastin is a highly insoluble protein component of the elastic fibers found in the ECM to provide elasticity and resilience to tissues requiring the ability to deform reversibly. Tissues rich in elastin include the aorta and large blood vessels (28–32% of the dry mass), lung (3–7%), elastic ligaments (50%), tendons (4%), and skin (2%) (Vrhovski and Weiss 1998; Debelle and Tamburro 1999). Tropoelastin, the precursor of elastin, is encoded by a single gene located on chromosome 7q11in humans and its alternative splicing results in at least 11 variants (Vrhovski and Weiss 1998). After minor post-translation modifications, tropoelastin is oxidized and covalently cross-linked by LysOX catalytic activity (Gibson et al. 1996; Kagan 1986) after which it is assembled into microfibers (Gibson et al. 1996).

LysOX is a tumor suppressor

The first direct evidence of the tumor suppressor activity of LysOX was demonstrated (Contente et al. 1990), and it identified a markedly down-regulated cDNA species upon transformation of mouse NIH 3T3 cells with LTR-c-H-ras. The expression level of this cDNA was restored when the transformed cell line (RS485) was treated with interferon to obtain a persistent revertant cell line (PR4). This cDNA species was named as ras recision gene (rrg). Contente et al. (1990) were the first to isolate an mRNA (called the ras recision gene) that was downregulated in ras-trans- formed fibroblasts. Persistent treatment of ras-transformed fibroblasts with IFNa/b yielded a revertant of the ras- transformed phenotype and a corresponding re-expression of the ras recision gene. It was later determined that the ras recision gene was, in fact, LysOX (Kenyon et al. 1991). Subsequently, it also demonstrated that the experimental downregulation of LysOX in normal rat kidney fibroblasts (NRKF) led to increased cellular proliferation and anchorage-independent growth, loss of PDGF and IGF-1 regulation, and constitutive activation of ras (Giampuzzi

Lysyl oxidase: a potential target for cancer therapy

et al. 2001). A non-orthotopic injection of LysOX knock out NRKF cells demonstrated increased tumorigenicity and metastasis. These investigators went on to demonstrate that the constitutive activation of ras (by downregulation of LysOX) led to increased expression of b-catenin and cyclin D1 through a noncanonical ras signaling pathway (Gia- mpuzzi et al. 2003b). Moreover, re-expression of LysOX in ras-transformed fibroblasts led to a decrease in the activa- tion of NF-jB, a potent transcription factor capable of regulating cell growth and neoplastic transformation (Jeay et al. 2003). The deactivation of NF-jB was not due to direct interaction with LysOX, but by the inhibition of Akt/ PI3K activation and membrane localization (a ras activated pathway). The most unanticipated results demonstrated that it was not LysOX catalytic activity that mediated the suppression of neoplastic transformation signaling in fibroblasts, but it was the 18-kDa LysOX-PP cleaved from pro-LysOX by BMP-1 (Palamakumbura et al. 2004). Although intracellular activity of the cleaved amino ter- minus of proLysOX is a recent finding, it is not novel as the cleaved procollagen N-propeptide has also been shown to function intracellularly to alter protein synthesis and phosphorylation, as well as cellular adhesion (Oganesian et al. 2006). In addition to oncogene-transformed fibro- blasts, a decrease in LysOX activity has also been observed in fibrosarcoma, choriocarcinoma, and rhabdomyosarcoma cell lines compared with normal fibroblast cell lines, which was subsequently shown to be due to low quantities of LysOX mRNA (Kuivaniemi et al. 1986a, b; Ha¨ma¨la¨inen et al. 1995). With the introduction of microarray analysis, LysOX has been shown to be modulated in various cancer cell lines and their corresponding tumor tissues. Thus, the majority of reports indicating alterations in LysOX expression have been limited to mRNA a transcript level, which does not always correlate with catalytic activity (Uzel et al. 2000). To date, a decrease in LysOX mRNA and/or protein has been observed in basal and squamous cell, bronchogenic, colon, esophageal, gastric, head and neck squamous cell, pancreatic, and prostatic carcinomas, as well as melanoma. However, only two reports have definitively demonstrated a tumor suppressor role for LysOX using in vitro/in vivo model systems. Downregu- lation of LysOX (stable antisense expression) in keratinocytes induced their invasion into the dermis of an in vitro skin equivalent model (Bouez et al. 2006). Interestingly, treatment of normal keratinocytes with bAPN did not induce invasion and suggests a role for LysOX-PP in tumor suppression in this model. Alterna- tively, LysOX protein may be capable of binding to novel target proteins outside of the catalytic domain to alter cell signaling involved in tumor progression. Stable transfec- tion of full-length LysOX cDNA into an intestinal-type gastric cancer cell line decreased proliferation and

anchorage-independent cell growth, as well as tumorigen- esis in non-orthotopically injected nude mice (Kaneda et al. 2004a, b). These studies have shown that LysOX acts as a potent tumor suppressor gene in fibroblasts, basal, and squamous cell and gastric carcinomas that occur through inhibiting intracellular signaling pathways known to induce neoplastic transformation. It remains to be determined whether the tumor suppressor activity of LysOX is as intimately involved in other cancers where down regulation of LysOX mRNA has been observed. Altered expression of other LysOX family members has been identified as well. LysOXL mRNA expression is downregulated in renal cell carcinoma cell lines in which the Von Hippel-Lindau (VHL) gene has been mutated, suggesting that loss of LysOXL expression is associated with oncogenesis of type 2B VHL disease (mutations in the elongin-binding region) (Tsuchiya et al. 2005). In addition, LysOXL expression was upregulated in wild-type p53 reconstituted lung ade- nocarcinoma cell lines (Kannan et al. 2001). Down- regulation of LysOXL mRNAwas observed in head and neck squamous cell carcinoma cell lines; however, more in-depth analyses are required to establish a tumor sup- pressor role for LysOXL and LysOXL2 in these cancers. The tumor suppressor activity of LysOX has been mapped to the pro-peptide region, and LysOX-PP inhibits tumor formation by breast cancer cells in mice (Paola et al. 2008) (Table 1).

LysOX is a metastasis promoter

The upregulation of LysOX mRNA in various cancer cell lines and their corresponding tumor tissues was demon- strated by microarray technology. To date, an increase in LysOX mRNA and/or protein has been observed in breast, central nervous system cancer cell lines, head and neck squamous cell, prostatic, clear cell renal cell, and lung carcinomas, and in melanoma and osteosarcoma cell lines, compared with their normal or non-aggressive neoplastic counterparts. Statistically significant clinical correlations between LysOX expression and tumor progression have been observed in breast (Erler et al. 2006), head and neck squamous cell (Erler et al. 2006), prostatic (Lapointe et al. 2004), and clear cell renal cell carcinomas (Stassar et al. 2001). LysOXL1 gene regulation is affected by an epige- netic mechanism that can be reversed by an inhibitor of DNA methyltransferase activity (Romain et al. 2010).The expression of high levels of LysOX mRNA and/or protein was a poor prognostic factor and was associated with poorly differentiated, high-grade tumors, increased recur- rence rates, and decreased overall survival. The role of LysOX in tumor progression has been most extensively studied in breast cancer using in vitro models of migration/

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Table 1 LysOX as a tumor suppressor gene: in vitro and in vivo studies

In vivo

In vitro

Inhibition of ras transformation (Di Donato et al. 1997) Stromal reactions in cancer (Bouez et al. 2006) Inhibition of breast cancer (Urashima et al. 2008) Inhibition of Choriocarcinoma (Ha¨ma¨la¨inen et al. 1995) In Esophageal cancer (He et al. 2002) Gastric cancer (Kaneda et al. 2004a, b) Lung cancer (Wu et al. 2007) Multiple endocrine neoplasia (MEN) (Watanabe et al. 2002) Ovarian cancer (Kaneda et al. 2004a, b) Prostate cancer (Ren et al. 1998) Rhabdomyosarcoma (Ha¨ma¨la¨inen et al. 1995)

Inhibition of ras (Csiszar et al. 1996) Inhibition of basal and squamous cell carcinoma (Bouez et al. 2006) Inhibition of bone cancer (Buchinger et al. 2008) Choriocarcinoma (Ha¨ma¨la¨inen et al. 1995) Inhibition of Colon Cancer (Csiszar et al. 2002) Fibrosarcoma (Ha¨ma¨la¨inen et al. 1995) Head and neck squamous cell carcinoma (HNSCC) (Rost et al. 2003) Lung cancer (Shames et al. 2006) Pancreatic cancer (Wu et al. 2007)

invasion and in in vivo tumorigenesis and metastasis mouse models. In malignant human breast carcinomas, LysOX was highly expressed in myofibroblasts and myo- epithelial cells surrounding the in situ tumor and in the reactive fibrosis facing the invasion front of infiltrating tumors (Peyrol et al. 1997). Upregulation of LysOXL2 mRNA and/or protein has been reported in breast, esoph- ageal, head and neck squamous cell, pancreatic, and prostatic carcinomas, melanoma, and E1A-immortalized kidney epithelial cell lines, compared with normal or poorly aggressive neoplastic counterparts. Chung and col- leagues demonstrated that increased LysOXL2 expression (along with the expression of 74 other genes) was signifi- cantly associated with high-risk head and neck squamous cell carcinoma and could be used as a predictive biomarker for high-risk patients (Chung et al. 2006). It has been demonstrated that stable expression of LysOXL2 in poorly invasive/non-metastatic MCF-7 breast cancer cells pro- duced estrogen-dependent tumors in orthotopically injected nude mice with many fibrotic foci and cells that were capable of invading the tumor pseudocapsule and into surrounding blood vessels, nerves, and muscle tissue (Akiri et al. 2003). Taken together, these reports demonstrate the potential of LysOXL2 to promote metastatic tumor pro- gression; however, more in-depth analyses are required to determine the mechanism in these cancers. In contrast, very few reports have demonstrated altered expression of Lys- OXL3 and LysOXL4 in cancers. At this time, very little is known about the biological function of these LysOX family members in normal cell processes (Fig. 2; Table 2).

Biosynthesis of LysOX

It has been demonstrated that the LysOX protein is known to be secreted into the extracellular space (Byers et al. 1980; Kuivaniemi et al. 1986a; Layman et al. 1972;

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1980 ; Kuivaniemi et al. 1986a ; Layman et al. 1972 ; 123 Fig. 2 LysOX

Fig. 2 LysOX regulation

Peltonen et al. 1983; Royce et al. 1980). The transport through the Golgi and to the cell membrane probably takes place in vesicles formed by budding of, and fusion with, the sub-cellular membranes (Kosonen et al. 1997; Rucker

et al. 1998). Human LysOX is synthesized as a 48-kDa

prepro-enzyme with a 21-amino-acid signal sequence at the

N terminus (Trackman et al. 1992). Following the N-ter-

minal glycosylation, the signal peptide is cleaved off and

the copper co-factor incorporates into the protein, resulting

in an intermediary 50 kDa pro-enzyme in the Golgi appa-

ratus which is then secreted to the extracellular space (Trackman et al. 1992; Layman et al. 1972). There the protein can be activated by a proteolytic cleavage between residues G168 and D-169, which is catalyzed by procol- lagen C-proteinase/BMP-1 (bone morphogenetic protein-1) (Cronshaw et al. 1995). The proteinase activation yields a mature enzyme of 30 kDa (Panchenko et al. 1996; Kagan and Li 2003) and 18 kDa N-terminal propeptide fragment.

Lysyl oxidase: a potential target for cancer therapy

Table 2 LysOX as a metastasis promoter gene: in vitro and in vivo studies

In vivo

In vitro

Promotion of tumor progression in breast cancer (reviewed in Payne et al. 2007).

Promotion of tumor progression in brain cancer (Freije et al. 2004)

Promotion of tumor progression in head and neck squamous cell carcinoma (HNSCC) (Erler et al. 2006; Le et al. 2007)

Promotion of tumor progression in lung cancer (Borczuk et al. 2005)

Promotion of tumor progression in renal cell carcinoma (RCC) (Korenaga et al. 2005)

Promotion of tumor progression in bone cancer (Fuchs et al. 2000)

Promotion of tumor progression in brain cancer (Ross et al. 2000)

Promotion of tumor progression in breast cancer (reviewed in Payne et al. 2007)

Promotion of tumor progression in cervical cancer (Erler et al. 2006)

Promotion of tumor progression in prostate cancer (Stewart et al. 2009)

Proteolytic processing and activation of LysOX

Mammalian BMP-1 proteinase family members (BMP-1, mTLD, mTLL-1, mTLL-2) have LysOX pro-enzyme pro- cessing activity (Uzel et al. 2001). These proteins are encoded by two genes. By alternative splicing, BMP1 gene codes BMP-1 and mammalian tolloid (mTLD) while the tolloid-related proteinases, tolloid-like 1 (mTLL-1) and tolloid-like 2 (mTLL-2) are encoded by mTll-1 gene (Uzel et al. 2001; Kessler et al. 1996; Prockop et al. 1998; Takahara et al. 1994). BMP-1 is a multifunctional enzyme as it was also discovered to have procollagen C-proteinase activity, and moreover its amino acid sequence was iden- tical to the one of procollagen C-proteinase (Kessler et al. 1996). In mouse embryonic fibroblasts, all four BMP-1 proteinases show procollagen-C proteinase activity and cleave the 50-kDa LysOX precursor in vitro. Nevertheless, BMP-1, above all members of the family, showed the highest proteinase activity on LysOX (Uzel et al. 2001).

Transcriptional regulation of LysOX

LysOX mRNA expression and protein activity are highly responsive to a variety of cytokines, growth factors, and intercellular messengers (Csiszar 2001). LysOX mRNA was down-regulated by bFGF in human gingival fibroblasts (Hong and Trackman 2002), and LysOX mRNA in rabbit retinal pigment epithelial cells (Feres-Filho et al. 1996; Omori et al. 2002), and in mouse osteoblastic cells (Feres- Filho et al. 1996). It was also down-regulated by inter- feron- (IF-) in rat aortic smooth muscle cells (Tan et al. 1996; Song et al. 2000), and by prostaglandin E2 (PGE2) in human embryonic smooth muscle cells (Roy et al. 1996), and from neonatal rat lung fibroblasts (Boak et al. 1994; Choung et al. 1998). Transforming growth factor-b1 (TGF- b1) up-regulated both LysOX mRNA and protein levels in human embryonic lung fibroblasts (Roy et al. 1996; Choung et al. 1998), human gingival fibroblasts (Hong

et al. 1999), and myofibroblast-like cells in the flexor reticulum of carpal tunnel syndrome patients (Bose et al. 2000). In rodents TGF-b1 induced up-regulation of LysOX mRNA and protein levels was found in neonatal rat lung fibroblasts (Boak et al. 1994; Koslowski et al. 2003), the osteoblastic mouse cell line MC3T3-E1 (Shibanuma et al. 1993; Feres-Filho et al. 1995). TGF-b regulation of LysOX activity was also reported in rat aortic smooth muscle cells (Shanley et al. 1997; Gacheru et al. 1997). Platelet-derived growth factor (PDGF) also up-regulated LysOX mRNA levels in rabbit retinal pigment epithelial cells (Omori et al. 2002) and rat vascular smooth muscle cells (Smith-Mungo and Kagan 2002; Green et al. 1995). Application of insulin- like growth factor-I (IGF-I) in rat oral tissue increased LysOX protein level (Trackman et al. 1998). Amongst hormones, follicle-stimulating hormone (FSH) decreased LysOX mRNA expression and activity in rat granulose cells, but testosterone increased both LysOX mRNA level and activity (Bronson et al. 1987; Harlow et al. 2003; Slee et al. 2001).

Dietary copper and LysOX production

LysOX activity showed that it is influenced directly by the amount of dietary copper over a wide physiologic range of intakes in growing animals (Opsahl et al. 1982). It also reported that lysyl oxidase activity varies by as much as five- to sixfold in response to dietary copper, ranging from 0 added Cu to 25 mg Cu/g diet (Opsahl et al. 1982). This observation has intrigued us because there is no compelling reason why an excess of dietary copper per se should increase LysOX activity above what might be needed for normal cross-linking (Opsahl et al. 1982; Romero-Chap- man et al. 1990; Rucker et al. 1996). For example, for optimal growth in chickens the copper requirement is 5–10 mg Cu/g diet (Opsahl et al. 1982). Decreased colla- gen cross-linking does not occur until the copper intake is substantially \1 mg Cu/g diet. Copper deficiency also has

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little or no effect on LysOX protein or LysOX mRNA concentrations in tissues (Rucker et al. 1996). LysOX expression is regulated by hypoxia-inducible factors (HIFs), and, hence, LysOX expression is often up- regulated in hypoxic breast and head and neck tumors and also in cardiovascular diseases (Cristina et al. 2008) and regulation of LysOX by statins could contribute to vascular protection and to the cardiovascular risk reduction (Cristina et al. 2009). Patients with high LysOX-expressing tumors have poor overall survival. Furthermore, inhibition of LysOX has been demonstrated to eliminate metastases in mice. Targeting LysOXL2 with an inhibitory monoclonal antibody (AB0023) has been reported efficacious in both primary and metastatic xenograft models of cancer, as well as in liver and lung fibrosis models (Barry-Hamilton et al. 2010) and also pro-BAPNs showed good levels of in vitro hypoxia-selective inhibition of LysOX activity (Carlotta et al. 2009). The LysOXL1 genetic predisposition is lim- ited to exfoliation glaucoma and does not include normal tension glaucoma (Wolf 2010). In conclusion, our present review reveals that Lysyl oxidase plays a significant role in cancer therapy. Several studies using plant products and natural products show that targeting LysOX could significantly reduce tumor pro- gression, metastasis, and angiogenesis. Some of the natural products that have shown significant results involve Bio- phytum sensitivum, amentoflavone, and b-carotene (Guruvayoorappan and Kuttan 2007, 2008a, b). The dis- covery of new drugs that can inhibit of the LysOX enzyme may be useful in preventing tumor progression and metastasis (Erler et al. 2009), and it can lead to open new approaches and directions for cancer therapy.

Acknowledgments The Valuable support of Dr. Patrick Gomez, Director, School of Biotechnology and Health Sciences, Karunya University is greatfully acknowledged.

References

Akiri G, Sabo E, Dafni H, Vadasz Z, Kartvelishvily Y, Gan N, Kessler O, Cohan T, Resnick M, Neeman M, Neufeld G (2003) Lysyl oxidase-related protein-1 promotes tumor fibrosis and tumor progression in vivo. Cancer Res 63:1657–1666 Bailey AJ (2001) Molecular mechanisms of ageing in connective tissues. Mech Ageing Dev 122:735–755 Barry-Hamilton V, Spangler R, Marshal LD, McCauley S, Rodriguez HM, Oyasu M, Mikels A, Vaysberg M, Ghermazien H, Wai C, Garcia CA, Velayo AC, Jorgensen B, Biermann D, Tsai D, Green J, Zaffryar-Eilot S, Holzer A, Ogg S, Thai D, Neufeld G, Van VP, Smith V (2010) Allosteric inhibition of lysyl oxidase- like-2 impedes the development of a pathologic microenviron- ment. Nat Med 16(9):1009–1017 Bateman JF, Cole WG, Pillow JJ, Ramshaw JA (1986) Induction of procollagen processing in fibroblast cultures by neutral poly- mers. J Biol Chem 261:4198–4203

123

Boak AM, Roy R, Berk J, Taylor L, Polgar P, Goldstein RH, Kagan HM (1994) Regulation of lysyl oxidase expression in lung fibroblasts by transforming growth factor-beta 1 and prostaglan- din E2. Am J Respir Cell Mol Biol 11:751–755 Borczuk AC, Kim HK, Yegen HA, Friedman RA, Powell CA (2005) Lung adenocarcinoma global profiling identifies type II trans- forming growth factor-beta receptor as a repressor of invasiveness. Am J Respir Crit Care Med 172(6):729–737 Bose KK, Chakraborty J, Khuder S, Smith-Mensah WH, Robinson J

(2000) Lysyl oxidase activity in the cells of flexor retinaculum of individuals with carpal tunnel syndrome. J Occup Environ Med

42:582–587

Bouez C, Reynaud C, Noblesse E, Thepot A, Gleyzal C, Kanitakis J,

Perrier E, Damour O, Sommer P (2006) The lysyl oxidase LOX is absent in basal and squamous cell carcinomas and its knockdown induces an invading phenotype in a skin equivalent model. Clin Cancer Res 12(5):1463–1469 Boyd CD, Mariani TJ, Kim Y, Csiszar K (1995) The size heteroge- neity of human lysyl oxidase mRNA is due to alternate polyadenylation site and not alternate exon usage. Mol Biol Rep 21:95–103 Bronson RE, Calaman SD, Traish AM, Kagan HM (1987) Stimulation of lysyl oxidase (EC 1.4.3.13) activity by testosterone and characterization of androgen receptors in cultured calf aorta smooth-muscle cells. Biochem J 244:317–323 Buchinger B, Spitzer S, Karlic H, Klaushofer K, Varga F (2008) Lysyl oxidase (LOX) mRNA expression and genes of the differentiated osteoblastic phenotype are upregulated in human osteosarcoma cells by suramin. Cancer Lett 265(1):45–54

Byers PH (2001) Folding defects in fibrillar collagens. Philos Trans R Soc Lond B Biol Sci 356:151–157 Byers PH, Siegel RC, Holbrook KA, Narayanan AS, Bornstein P, Hall JG (1980) X-linked cutis laxa: defective cross-link formation in collagen due to decreased lysyl oxidase activity. N Engl J Med

303:61–65

Carlotta G, Tiziana F, Janine TE, Amato JG, Marco M, Filippo M

(2009) Bioreductively activated lysyl oxidase inhibitors against hypoxic tumours. ChemMedChem 4:1590–1594 Casey ML, MacDonald PC (1997) Lysyl oxidase (ras recision gene) expression in human amnion: ontogeny and cellular localization.

J Clin Endocrinol Metab 82:167–172

Chang YS, Svinarich DM, Yang TP, Krawetz SA (1993) The mouse lysyl oxidase gene (Lox) resides on chromosome 18. Cytogenet Cell Genet 63:47–49 Chanoki M, Ishii M, Kobayashi H, Fushida H, Yashiro N, Hamada T, Ooshima A (1995) Increased expression of lysyl oxidase in skin with scleroderma. Br J Dermatol 133:710–715

Choung J, Taylor L, Thomas K, Zhou X, Kagan H, Yang X, Polgar P (1998) Role of EP2 receptors and cAMP in prostaglandin E2 regulated expression of type I collagen alpha1, lysyl oxidase, and cycloox ygenase-1 genes in human embryo lung fibroblasts.

J Cell Biochem 71:254–263

Chung CH, Parker JS, Ely K, Carter J, Yi Y, Murphy BA, Ang KK, El-Naggar AK, Zanation M, Cmelak AJ, Levy S, Slebos RJ, Yarbrough WG (2006) Gene expression profiles identify epithelial-to-mesenchymal transition and activation of nuclear factor-kB signaling as characteristics of a high-risk head and neck squamous cell carcinoma. Cancer Res 66:8210–8218

Colpaert C, Vermeulen P, Van Marck E, Dirix L (2001) The presence of a fibrotic focus is an independent predictor of early metastasis in lymph node-negative breast cancer patients. Am J Surg Pathol

25:1557

Contente S, Kenyon K, Rimoldi D, Friedman RM (1990) Expression of gene rrg is associated with reversion of NIH 3T3 transformed by LTR-c-H-ras. Science 249:796–798

Lysyl oxidase: a potential target for cancer therapy

Contente S, Csiszar K, Kenyon K, Friedman RM (1993) Structure of the mouse lysyl oxidase gene. Genomics 16:395–400 Cristina R, Jose´ MG, Berta R, Javier FA, Anna G, Lina B (2008) Regulation of lysyl oxidase in vascular cells: lysyl oxidase as a new player in cardiovascular diseases. Cardiovasc Res 79(1):

7–13

Cristina R, Jose´ MG, Berta R, Javier FA, Anna G, Sonia SG, Lina B (2009) Statins normalize vascular lysyl oxidase down-regulation induced by proatherogenic risk factors. Cardiovasc Res

83(3):595–603

Cronlund AL, Kagan HM (1986) Comparison of lysyl oxidase from bovine lung and aorta. Connect Tissue Res 15:173–185 Cronshaw AD, Fothergill-Gilmore LA, Hulmes DJ (1995) The proteolytic processing site of the precursor of lysyl oxidase. Biochem J 306:279–284 Csiszar K (2001) Lysyl oxidases: a novel multifunctional amine oxidase family. Prog Nucleic Acid Res Mol Biol 70:1–32 Csiszar K, Entersz I, Trackman PC, Samid D, Boyd CD (1996) Functional analysis of the promoter and first intron of the human lysyl oxidase gene. Mol Biol Rep 23(2):97–108 Csiszar K, Fong SF, Ujfalusi A, Krawetz SA, Salvati EP, Mackenzie JW, Boyd CD (2002) Somatic mutations of the lysyl oxidase gene on chromosome 5q23.1 in colorectal tumors. Int J Cancer

97(5):636–642

Debelle L, Tamburro AM (1999) Elastin: molecular description and function. Int J Biochem Cell Biol 31:261–272 Decitre M, Gleyzal C, Raccurt M, Peyrol S, Aubert-Foucher E, Csiszar K, Sommer P (1998) Lysyl oxidase-like protein localizes to sites of de novo fibrinogenesis in fibrosis and in the early stromal reaction of ductal breast carcinomas. Lab Invest

78:143–151

Di Donato A, Lacal JC, Di Duca M, Giampuzzi M, Ghiggeri G, Gusmano R (1997) Micro-injection of recombinant lysyl oxidase blocks oncogenic p21-Ha-Ras and progesterone effects on Xenopus laevis oocyte maturation. FEBS Lett 419(1):63–68 Duffy MJ, Maguire TM, Hill A, McDermott E, O’Higgins N (2000) Metalloproteinases: role in breast carcinogenesis, invasion and metastasis. Breast Cancer Res 2:252–257 Ellenrieder V, Alber B, Lacher U, Hendler SF, Menke A, Boeck W, Wagner M, Wilda M, Friess H, Buchler M, Adler G, Gress TM (2000) Role of MT-MMPs and MMP-2 in pancreatic cancer progression. Int J Cancer 85:14–20 Erler JT, Bennewith KL, Nicolau M, Dornhofer N, Kong C, Le QT, Chi JT, Jeffrey SS, Giaccia AJ (2006) Lysyl oxidase is essential for hypoxia-induced metastasis. Nature 440(7088):1222–1226 Erler JT, Bennewith KL, Cox TR, Lang G, Bird D, Koong A, Le QT, Giaccia AJ (2009) Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premet- astatic niche. Cancer Cell 15(1):35–44 Faina R, Frederick TG (2010) Modeling Cu(II) binding to peptides using the extensible systematic force field. Bioinorgan Chem Appl 2010:724210. doi:10.1155/2010/724210 Feres-Filho EJ, Choi YJ, Han X, Takala TE, Trackman PC (1995) Pre- and post-translational regulation of lysyl oxidase by transforming growth factor-beta 1 in osteoblastic MC3T3-E1 cells. J Biol Chem 270:30797–30803 Feres-Filho EJ, Menassa GB, Trackman PC (1996) Regulation of lysyl oxidase by basic fibroblast growth factor in osteoblastic MC3T3-E1 cells. J Biol Chem 271:6411–6416 Fitzgerald J, Morgelin M, Selan C, Wiberg C, Keene DR, Lamande SR, Bateman JF (2001) The N-terminal N5 subdomain of the alpha 3(VI) chain is important for collagen VI microfibril formation. J Biol Chem 276:187–193 Fogelgren B, Polgar N, Szauter KM, Ujfaludi Z, Laczko R, Fong KS, Csiszar K (2005) Cellular fibronectin binds to lysyl oxidase with

high affinity and is critical for its proteolytic activation. J Biol Chem 280:24690–24697 Freije WA, Castro-Vargas FE, Fang Z, Horvath S, Cloughesy T, Liau LM, Mischel PS, Nelson SF (2004) Gene expression profiling of gliomas strongly predicts survival. Cancer Res 64(18):6503–6510 Fuchs B, Zhang K, Bolander ME, Sarkar G (2000) Identification of differentially expressed genes by mutually subtracted RNA fingerprinting. Anal Biochem 286(1):91–98 Fushida-Takemura H, Fukuda M, Maekawa N, Chanoki M, Kobay- ashi H, Yashiro N, Ishii M, Hamada T, Otani S, Ooshima A (1996) Detection of lysyl oxidase gene expression in rat skin during wound healing. Arch Dermatol Res 288:7–10 Gacheru SN, Thomas KM, Murray SA, Csiszar K, Smith-Mungo LI, Kagan HM (1997) Transcriptional and post-transcriptional control of lysyl oxidase expression in vascular smooth muscle cells: effects of TGF-beta 1 and serum deprivation. J Cell Biochem 65:395–407 Giampuzzi M, Botti G, Di Duca M, Arata L, Ghiggeri G, Gusmano R, Ravazzolo R, Di Donato A (2000) Lysyl oxidase activates the transcription activity of human collagen III promoter: possible involvement of Ku antigen. J Biol Chem 275:36341–36349 Giampuzzi M, Botti G, Cilli M, Gusmano R, Borel A, Sommer P, Di Donato A (2001) Down-regulation of lysyl oxidase-induced tumorigenic transformation in NRK-49F cells characterized by constitutive activation of ras proto-oncogene. J Biol Chem

276:29226–29232

Giampuzzi M, Oleggin R, Di Donato A (2003a) Demonstration of in vitro interaction between tumor suppressor lysyl oxidase and histones H1 and H2: definition of the regions involved. Biochim Biophys Acta 1647:245–251 Giampuzzi M, Oleggini R, Di Donato A (2003b) Altered adhesion features and signal transduction in NRK-49F cells transformed by down-regulation of lysyl oxidase. Biochim Biophys Acta

1647:239–244

Giampuzzi M, Oleggini R, Albanese C, Pestell R, Di Donato A (2005) b-catenin signaling and regulation of cyclin D1 promoter in NRK-49F cells transformed by down-regulation of the tumor suppressor lysyl oxidase. Biochim Biophys Acta

1745:370–381

Gibson MA, Hatzinikolas G, Kumaratilake JS, Sandberg LB, Nicholl JK, Sutherland GR, Cleary EG (1996) Further characterization of proteins associated with elastic fiber microfibrils including the molecular cloning of MAGP-2 (MP25). J Biol Chem 271:

1096–1103

Green RS, Lieb ME, Weintraub AS, Gacheru SN, Rosenfield CL, Shah S, Kagan HM, Taubman MB (1995) Identification of lysyl oxidase and other platelet-derived growth factor-inducible genes in vascular smooth muscle cells by differential screening. Lab Invest 73:476–482 Guruvayoorappan C, Kuttan G (2007) Beta-carotene inhibits tumor- specific angiogenesis by altering the cytokine profile and inhibits the nuclear translocation of transcription factors in B16F-10 melanoma cells. Integr Cancer Ther 6:258–270 Guruvayoorappan C, Kuttan G (2008a) Biophytum sensitivum (L.) DC inhibits tumor cell invasion and metastasis through a mechanism involving regulation of MMPs, prolyl hydroxylase, lysyl oxidase, nm23, ERK-1, ERK-2, STAT-1, and proinflammatory cytokine gene expression in metastatic lung tissue. Integr Cancer Ther 7:42–50 Guruvayoorappan C, Kuttan G (2008b) Amentoflavone inhibits experimental tumor metastasis through a regulatory mechanism involving MMP-2, MMP-9, prolyl hydroxylase, lysyl oxidase, VEGF, ERK-1, ERK-2, STAT-1, NM23 and cytokines in lung tissues of C57BL/6 mice. Immunopharmacol Immunotoxicol

30:711–727

123

Siddikuzzaman et al.

Hajnal A, Klemenz R, Schafer R (1993) Up-regulation of lysyl oxidase in spontaneous revertants of H-ras-transformed rat fibroblasts. Cancer Res 53:4670–4675 Hamalainen ER, Jones TA, Sheer D, Taskinen K, Pihlajaniemi T, Kivirikko KI (1991) Molecular cloning of human lysyl oxidase and assignment of the gene to chromosome 5q23.3–31.2. Genomics 11:508–516 Hamalainen ER, Kemppainen R, Pihlajaniemi T, Kivirikko KI (1993) Structure of the human lysyl oxidase gene. Genomics

17:544–548

Ha¨ma¨la¨inen ER, Kemppainen R, Kuivaniemi H, Tromp G, Vaheri A, Pihlajaniemi T, Kivirikko KI (1995) Quantitative polymerase chain reaction of lysyl oxidase mRNA in malignantly trans- formed human cell lines demonstrates that their low lysyl oxidase activity is due to low quantities of its mRNA and low levels of transcription of the respective gene. J Biol Chem

270(37):21590–21593

Harlow CR, Rae M, Davidson L, Trackman PC, Hillier SG (2003) Lysyl oxidase gene expression and enzyme activity in the rat ovary: regulation by follicle-stimulating hormone, androgen, and transforming growth factor-beta superfamily members in vitro. Endocrinology 144:154–162 Hasebe T, Mukai K, Tsuda H, Ochiai A (2000) New prognostic histological parameter of invasive ductal carcinoma of the breast: clinicopathological significance of fibrotic focus. Pathol Int 50:263–272 He J, Tang HJ, Wang YY, Xiong MH, Zhou F, Shao K, Li TP (2002) Expression of lysyl oxidase gene in upper digestive tract carcinomas and its clinical significance. Ai Zheng 21(6):

671–674

Hong HH, Trackman PC (2002) Cytokine regulation of gingival fibroblast lysyl oxidase, collagen, and elastin. J Periodontol

73:145–152

Hong HH, Uzel MI, Duan C, Sheff MC, Trackman PC (1999) Regulation of lysyl oxidase, collagen, and connective tissue growth factor by TGF-beta1 and detection in human gingival. Lab Invest 79:1655–1667 Huang Y, Dai J, Tang R, Zhao W, Zhou Z, Wang W, Ying K, Xie Y, Mao Y (2001) Cloning and characterization of a human lysyl oxidase-like 3 gene (hLOXL3). Matrix Biol 20:153–157 Hynes RO (2002) A reevaluation of integrins as regulators of angiogenesis. Nat Med 8:918–921 Jansen MK, Csiszar K (2007) Intracellular localization of the matrix enzyme lysyl oxidase in polarized epithelial cells. Matrix Biol

26:136–139

Jeay S, Pianetti S, Kagan HM, Sonenshein GE (2003) Lysyl oxidase inhibits ras-mediated transformation by preventing activation of NF-Kb. Mol Cell Biol 23:2251–2263 Jourdan-Le Saux C, Gleyzal C, Garnier JM, Peraldi M, Sommer P, Grimaud JA (1994) Lysyl oxidase cDNA of myofibroblast from mouse fibrotic liver. Biochem Biophys Res Commun 199:

587–592

Jourdan-Le Saux C, Tronecker H, Bogic L, Bryant-Greenwood GD, Boyd CD, Csiszar K (1999) The LOXL2 gene encodes a new lysyl oxidase-like protein and is expressed at high levels in reproductive tissues. J. Biol. Chem 274:12939–12944 Juliano RL (2002) Signal transduction by cell adhesion receptors and the cytoskeleton: functions of integrins, cadherins, selectins, and immunoglobulin-superfamily members. Annu Rev Pharmacol Toxicol 42:283–323 Kagan HM (1986) Characterization and regulation of lysyl oxidase. In: Mecham RP (ed) Biology of extracellular matrix. Academic Press, Orlando, pp 321–389 Kagan HM (1994) Lysyl oxidase: mechanism, regulation and relationship to liver fibrosis. Pathol Res Pract 190:910–919

123

Kagan HM, Cai P (1995) Isolation of active site peptides of lysyl oxidase. Methods Enzymol 258:122–132 Kagan HM, Li W (2003) Lysyl oxidase: properties, specificity, and biological roles inside and outside of the cell. J Cell Biochem

88:660–672

Kagan HM, Raghavan J, Hollander W (1981) Changes in aortic lysyl oxidase activity in diet-induced atherosclerosis in the rabbit. Arteriosclerosis 1:287–291 Kagan HM, Williams MA, Calaman SD, Berkowitz EM (1983) Histone H1 is a substrate for lysyl oxidase and contains endogenous sodium borotritide-reducible residues. Biochem Biophys Res Commun 115:186–192 Kagan HM, Williams MA, Williamson PR, Anderson JM (1984) Influence of sequence and charge on the specificity of lysyl oxidase toward protein and synthetic peptide substrates. J Biol Chem 259:11203–11207 Kaneda A, Wakazono K, Tsukamoto T, Watanabe N, Yagi Y, Tatematsu M, Kaminishi M, Sugimura T, Ushijima T (2004a) Lysyl oxidase is a tumor suppressor gene inactivated by methylation and loss of heterozygosity in human gastric cancers. Cancer Res 64:6410–6415 Kaneda A, Wakazono K, Tsukamoto T, Watanabe N, Yagi Y, Tatematsu M, Kaminishi M, Sugimura T, Ushijima T (2004b) Lysyl oxidase is a tumor suppressor gene inactivated by methylation and loss of heterozygosity in human gastric cancers. Cancer Res 64(18):6410–6415 Kannan K, Amariglio N, Rechavi G, Jakob-Hirsch J, Kela I, Kaminski N, Getz G, Domany E, Givol D (2001) DNA microarrays identification of primary and secondary target genes regulated by p53. Oncogene 20:2225–2234 Kenyon K, Contente S, Trackman PC, Tang J, Kagan HM, Friedman RM (1991) Lysyl oxidase and rrg messenger RNA. Science

253:802

Kenyon K, Modi WS, Contente S, Friedman RM (1993) A novel human cDNA with a predicted protein similar to lysyl oxidase maps to chromosome 15q24–q25. J Biol Chem 268:18435–

18437

Kessler E, Takahara K, Biniaminov L, Brusel M, Greenspan DS (1996) Bone morphogenetic protein-1: the type I procollagen C-proteinase. Science 271:360–362 Khakoo A, Thomas R, Trompeter R, Duffy P, Price R, Pope FM (1997) Congenital cutis laxa and lysyl oxidase deficiency. Clin Genet 51:109–114 Kim Y, Boyd CD, Csiszar K (1995) A new gene with sequence and structural similarity to the gene encoding human lysyl oxidase. J Biol Chem 270:7176–7182 Kirschmann DA, Seftor EA, Fong SF, Nieva DR, Sullivan CM, Edwards EM, Sommer P, Csiszar K, Hendrix MJ (2002) A molecular role for lysyl oxidase in breast cancer invasion. Cancer Res 62:4478–4483 Koch M, Foley JE, Hahn R, Zhou P, Burgeson RE, Gerecke DR, Gordon MK (2001) alpha 1(Xx) collagen, a new member of the collagen subfamily, fibril-associated collagens with interrupted triple helices. J Biol Chem 276:23120–23126 Korenaga Y, Matsuyama H, Hirata H, Nagao K, Ohmi C, Sakano S, Yoshihiro S, Naito K (2005) Smoking may cause genetic alterations at 5q22.2 approximately q23.1 in clear-cell renal cell carcinoma. Cancer Genet Cytogenet 163(1):7–11 Koslowski R, Seidel D, Kuhlisch E, Knoch KP (2003) Evidence for the involvement of TGF-beta and PDGF in the regulation of prolyl 4-hydroxylase and lysyloxidase in cultured rat lung fibroblasts. Exp Toxicol Pathol 55:257–264 Kosonen T, Uriu-Hare JY, Clegg MS, Keen CL, Rucker RB (1997) Incorporation of copper into lysyl oxidase. Biochem J 327:

283–289

Lysyl oxidase: a potential target for cancer therapy

Krzyzosiak WJ, Shindo-Okada N, Teshima H, Nakajima K, Nishim-

ura S (1992) Isolation of genes specifically expressed in flat

revertant cells derived from activated ras-transformed NIH 3T3 cells by treatment with azatyrosine. Proc Natl Acad Sci

89:4879–4883

Kuivaniemi H, Savolainen ER, Kivirikko KI (1984) Human placental

lysyl oxidase. Purification, partial characterization, and prepara- tion of two specific antisera to the enzyme. J Biol Chem

259:6996–7002

Kuivaniemi H, Peltonen L, Kivirikko KI (1985) Type IX Ehlers– Danlos syndrome and Menkes syndrome: the decrease in lysyl oxidase activity is associated with a corresponding deficiency in

the enzyme protein. Am J Hum Genet 37:798–808

Kuivaniemi H, Ala-Kokko L, Kivirikko KI (1986a) Secretion of lysyl oxidase by cultured human skin fibroblasts and effects of monensin, nigericin, tunicamycin and colchicines. Biochim Biophys Acta 883:326–334 Kuivaniemi H, Korhonen RM, Vaheri A, Kivirikko KI (1986b) Deficient production of lysyl oxidase in cultures of malignantly transformed human cells. FEBS Lett 195:261–264

Lapointe J, Li C, Higgins JP, van de Rijn M, Bair E, Montgomery K, Ferrari M, Egevad L, Rayford W, Bergerheim U, Ekman P, DeMarzo AM, Tibshirani R, Botstein D, Brown PO, Brooks JD, Pollack JR (2004) Gene expression profiling identifies clinically relevant subtypes of prostate cancer. Proc Natl Acad Sci

101:811–816

Mock BA, Contente S, Kenyon K, Friedman RM, Kozak CA (1992) The gene for lysyl oxidase maps to mouse chromosome 18.

Genomics 14:822–823 Myllyharju J, Kivirikko KI (2001) Collagens and collagen-related diseases. Ann Med 33:7–21 Nagan N, Kagan HM (1994) Modulation of lysyl oxidase activity toward peptidyl lysine by vicinal dicarboxylic amino acid residues. Implications for collagen cross-linking. J Biol Chem

269:22366–22371

Nellaiappan K, Risitano A, Liu G, Nicklas G, Kagan HM (2000) Fully

processed lysyl oxidase catalyst translocates from the extracel- lular space into nuclei of aortic smoothmuscle cells. J Cell Biochem 79:576–582 Nelson JM, Diegelmann RF, Cohen IK (1988) Effect of b- aminopropionitrile and ascorbate on fibroblast migration. Proc Soc Exp Biol Med 188:346–352 Nishimura R, Hasebe T, Tsubono Y, Ono M, Sugitoh M, Arai T, Mukai K (1998) The fibrotic focus in advanced colorectal carcinoma: a hitherto unrecognized histological predictor for liver metastasis. Virchows Arch 433:517–522 Oganesian A, Au S, Horst JA, Holzhausen LC, Macy AJ, Pace JM (2006) The NH2-terminal propeptide of type I procollagen acts intracellularly to modulate cell function. J Biol Chem

281:38507–38518

Ohkawa K, Fujii K, Nishida A, Yamauchi T, Ishibashi H, Yamamoto

H (2001) Lysyl oxidase-catalyzed cross-linking and insolubili-

Layman DL, Narayanan AS, Martin GR (1972) The production of lysyl oxidase by human fibroblasts in culture. Arch Biochem Biophys 149:97–101 Lazarus HM, Cruikshank WW, Narasimhan N, Kagan HM, Center DM (1994) Induction of human monocyte motility by lysyl oxidase. Mat Biol 14:727–731

zation reactions of Lys-containing polypeptides and synthetic adhesive proteins. Biomacromolecules 2:773–779

Omori K, Fujiseki Y, Suzukawa J, Inagaki C (2002) Regulation of the expression of lysyl oxidase mRNA in cultured rabbit retinal pigment epithelium cells. Matrix Biol 21:337–348 Ooshima A, Midorikawa O (1977) Increased lysyl oxidase activity in

Le

QT, Kong C, Lavori PW, O’byrne K, Erler JT, Huang X, Chen Y, Cao H, Tibshirani R, Denko N, Giaccia AJ, Koong AC (2007) Expression and prognostic significance of a panel of tissue hypoxia markers in head-and-neck squamous cell carcinomas. Int J Radiat Oncol Biol Phys 69(1):167–175

blood vessels of hypertensive rats and effect of b-aminopropio- nitrile on arteriosclerosis. Jpn Circ J 41:1337–1340 Opsahl W, Zeronian H, Ellison M, Lewis D, Rucker RB, Riggins RS (1982) Role of copper in collagen cross-linking and its influence on selected mechanical properties of chick bone and tendon.

Li

W, Nellaiappan K, Strassmaier T, Graham L, Thomas KM, Kagan

J

Nutr 112:708–716

HM (1997) Localization and activity of lysyl oxidase within nuclei of fibrogenic cells. Proc Natl Acad Sci 94:12817–12822 Li W, Liu G, Chou IN, Kagan HM (2000) Hydrogen peroxide-

mediated, lysyl oxidase-dependent chemotaxis of vascular smooth muscle cells. J Cell Biol 78:550–557

Li W, Nugent MA, Zhao Y, Chau AN, Li SJ, Chou IN, Liu G, Kagan

HM (2003) Lysyl oxidase oxidizes basic fibroblast growth factor

and inactivates its mitogenic potential. J Cell Biochem

88:152–164

Light ND, Bailey AJ (1980) The chemistry of the collagen cross-

links. Purification and characterization of cross-linked polymeric peptide material from mature collagen containing unknown amino acids. Biochem J 185:373–381 Lucero HA, Kagan HM (2006) Lysyl oxidase: an oxidative enzyme

and effector of cell function. Cell Mol Life Sci 63:2304–2316

Maki JM, Tikkanen H, Kivirikko KI (2001) Cloning and character-

ization of a fifth human lysyl oxidase isoenzyme: the third

member of the lysyl oxidase-related subfamily with four scav- enger receptor cysteine-rich domains. Matrix Biol 20:493–496 Mariani TJ, Trackman PC, Kagan HM, Eddy RL, Shows TB, Bo yd

CD (1992) The complete derived amino acid sequence of human

lysyl oxidase and assignment of the gene to chromosome 5 (extensive sequence homology with the murine ras recision gene). Matrix 12:242–248 Mello MLS, Contente S, Vidal BC, Planding W, Schenck U (1995) Modulation of ras transformation affecting chromatin supraor- ganization as assessed by image analysis. Exp Cell Res

22:374–382

Palamakumbura AH, Jeay S, Guo Y, Pischon N, Sommer P,

Sonenshein GE, Trackman PC (2004) The propeptide domain

of lysyl oxidase induces phenotypic reversion of ras-transformed

cells. J Biol Chem 279:40593–40600 Panchenko MV, Stetler-Stevenson WG, Trubetskoy OV, Gacheru SN,

Kagan HM (1996) Metalloproteinase activity secreted by fibrogenic cells in the processing of prolysyl oxidase. Potential role of procollagen C-proteinase. J Biol Chem 271:7113–7119 Paola AH, Siddharth V, Siddika Selva S, Dan Y, Cynthia St H, Ying G, Amitha HP, Barbara MS, Katya R, Philip CT (2008) Lysyl oxidase propeptide inhibits smooth muscle cell signaling and proliferation. Biochem Biophys Res Commun 366(1):

156–161

Payne SL, Hendrix MJ, Kirschmann DA (2007) Paradoxical roles for lysyl oxidases in cancer––a prospect. J Cell Biochem

101(6):1338–1354

Peltonen L, Kuivaniemi H, Palotie A, Horn N, Kaitila I, Kivirikko KI (1983) Alterations in copper and collagen metabolism in the Menkes syndrome and a new subtype of the Ehlers–Danlos syndrome. Biochemistry 22:6156–6163 Peyrol S, Raccurt M, Gerard F, Gleyzal C, Grimaud JA, Sommer P (1997) Lysyl oxidase gene expression in the stromal reaction to in situ and invasive ductal breast carcinoma. Am J Pathol

150:497–507

Pinnell SR (1982) Molecular defects in the Ehlers–Danlos syndrome.

J Invest Dermatol 79:90s–92s

Pinnell SR, Martin GR (1968) The cross-linking of collagen and elastin: enzymatic conversion of lysine in peptide linkage to -

123

Siddikuzzaman et al.

aminoadipic-delta-semialdehyde (allysine) by an extract from bone. Proc Natl Acad Sci 61:708–716 Polgar N, Fogelgren B, Shipley JM, Csiszar K (2007) Lysyl oxidase

interact with hormone placental lactogen and synergistically promotes breast epithelial cell proliferation and migration. J Biol Chem 282:3262–3272 Prockop DJ, Sieron AL, Li SW (1998) Procollagen N-proteinase and procollagen C-proteinase. Two unusual metalloproteinases that

are essential for procollagen processing probably have important

roles in development and cell signaling. Matrix Biol 16:399–408 Reiser K, McCormick RJ, Rucker RB (1992) Enzymatic and nonenzymatic cross-linking of collagen and elastin. FASEB J

6:2439–2449

Ren C, Yang G, Timme TL, Wheeler TM, Thompson TC (1998) Reduced lysyl oxidase messenger RNA levels in experimental

and human prostate cancer. Cancer Res 58(6):1285–1290 Romain D, Vale´rie C, Ge´raldine A, Vale´rie A, Martine D, Isabelle R, Andre´ M, Odile D, Pascal S (2010) Epigenetic silencing of lysyl oxidase-like-1 through DNA hypermethylation in an autosomal recessive cutis laxa case. J Invest Dermatol 130:2594–2601 Romero-Chapman N, Lee J, Tinker D, Uriu-Hare JY, Keen CL, Rucker RB (1990) Lysyl oxidase: purification, properties and influence of dietary copper on accumulation and functional activity in rat skin. Biochem J 275:657–662 Ross DT, Scherf U, Eisen MB, Perou CM, Rees C, Spellman P, Iyer

V, Jeffrey SS, Van de Rijn M, Waltham M, Pergamenschikov A,

Lee JC, Lashkari D, Shalon D, Myers TG, Weinstein JN, Botstein D, Brown PO (2000) Systematic variation in gene expression patterns in human cancer cell lines. Nat Genet

24(3):227–235

Rost T, Pyritz V, Rathcke IO, Gorogh T, Dunne AA, Werner JA (2003) Reduction of LOX- and LOXL2-mRNA expression in head and neck squamous cell carcinomas. Anticancer Res

23(2B):1565–1573

Roy R, Polgar P, Wang Y, Goldstein RH, Taylor L, Kagan HM (1996) Regulation of lysyl oxidase and cyclooxygenase expres- sion in human lung fibroblasts: interactions among TGF-beta, IL-1 beta, and prostaglandin E. J Cell Biochem 62:411–417 Royce PM, Camakaris J, Danks DM (1980) Reduced lysyl oxidase activity in skin fibroblasts from patients with Menkes’ syndrome. Biochem J 192:579–586 Rucker RB, Romero-Chapman N, Wong T, Lee J, Steinberg FM, Mcgee C, Clegg MS, Reiser K, Kosonen T, Uriu-Hare JY, Murphy J, Keen CL (1996) Modulation of lysyl oxidase by dietary copper in rats. J Nutr 126:51–60 Rucker RB, Kosonen T, Clegg MS, Mitchell AE, Rucker BR, Uriu- Hare JY, Keen CL (1998) Copper, lysyl oxidase, and extracel- lular matrix protein cross-linking. Am J Clin Nutr 67:996–1002

Saito H, Papaconstantinou J, Sato H, Goldstein S (1997) Regulation

of a novel gene encoding a lysyl oxidase-related protein in

cellular adhesion and senescence. J Biol Chem 272:8157–8160 Sanada H, Shikata J, Hamamoto H, Ueba Y, Yamamuro T, Takeda T (1978) Changes in collagen cross-linking and lysyl oxidase by estrogen. Biochim Biophys Acta 541:408–413 Sawada S, Murakami K, Murata J, Tsukada K, Saiki I (2001)

Accumulation of extracellular matrix in the liver induces high metastatic potential of hepatocellular carcinoma to the lung. Int J Oncol 19:65–70 Schuppan D, Ruehl M, Somasundaram R, Hahn EG (2001) Matrix as

a modulator of hepatic fibrogenesis. Semin Liver Dis

21:351–372

Shackleton DR, Hulmes DJ (1990) Purification of lysyl oxidase from

piglet skin by selective interaction with Sephacryl S-200. Biochem J 266:917–919 Shames DS, Girard L, Gao B, Sato M, Lewis CM, Shivapurkar N, Jiang A, Perou CM, Kim YH, Pollack JR, Fong KM, Lam CL,

123

Wong M, Shyr Y, Nanda R, Olopade OI, Gerald W, Euhus DM, Shay JW, Gazdar AF, Minna JD (2006) A genome-wide screen for promoter methylation in lung cancer identifies novel methylation markers for multiple malignancies. PLoS Med

3(12):e486

Shanley CJ, Gharaee-Kermani M, Sarkar R, Welling TH, Kriegel A, Ford JW, Stanley JC, Phan SH (1997) Transforming growth factor-beta 1 increases lysyl oxidase enzyme activity and mRNA in rat aortic smooth muscle cells. J Vasc Surg 25:446–452 Shibanuma M, Mashimo J, Mita A, Kuroki T, Nose K (1993) Cloning from a mouse osteoblastic cell line of a set of transforming- growth-factor-beta 1-regulated genes, one of which seems to encode a follistatin-related polypeptide. Eur J Biochem 217:13–19 Siegel RC (1974) Biosynthesis of collagen crosslinks: increased activity of purified lysyl oxidase with reconstituted collagen fibrils. Proc Natl Acad Sci 71:4826–4830 Slee RB, Hillier SG, Largue P, Harlow CR, Miele G, Clinton M (2001) Differentiation-dependent expression of connective tissue growth factor and lysyl oxidase messenger ribonucleic acids in rat granulosa cells. Endocrinology 142:1082–1089 Smith-Mungo LI, Kagan HM (1998) Lysyl oxidase: properties, regulation and multiple functions in biology. Matrix Biol

16:387–398

Smith-Mungo LI, Kagan HM (2002) PKC-MEK-MAPK-dependent signal transduction pathway mediates the stimulation of lysyl oxidase expression by serum and PDGF in rat aortic smooth muscle cells. J Cell Biochem 85:775–784 Sommer P, Gleyzal C, Raccurt M, Delbourg M, Serrar M, Joazeiro P, Peyrol S, Kagan HM, Trackman PC, Grimaud JA (1993) Transient expression of lysyl oxidase by liver myofibroblasts in murine schistosomiasis. Lab Invest 69:460–470 Song YL, Ford JW, Gordon D, Shanley CJ (2000) Regulation of lysyl oxidase by interferon-gamma in rat aortic smooth muscle cells. Arterioscler Thromb Vasc Biol 20:982–988 Stamenkovic I (2000) Matrix metalloproteinases in tumor invasion and metastasis. Semin Cancer Biol 10:415–433 Stassar MJ, Devitt G, Brosius M, Rinnab L, Prang J, Schradin T, Simon J, Petersen S, Kopp-Schneider A, Zoller M (2001) Identification of human renal cell carcinoma associated genes by suppression subtractive hybridization. Br J Cancer

85:1372–1382

Stassen FL (1976) Properties of highly purified lysyl oxidase from embryonic chick cartilage. Biochim Biophys Acta 438:49–60 Stewart GD, Nanda J, Brown DJ, Riddick AC, Ross JA, Habib FK (2009) NO-sulindac inhibits the hypoxia response of PC-3 prostate cancer cells via the Akt signalling pathway. Int J Cancer

124(1):223–232

Takahara K, Lyons GE, Greenspan DS (1994) Bone morphogenetic protein-1 and a mammalian tolloid homologue (mTld) are encoded by alternatively spliced transcripts which are differen- tially expressed in some tissues. J Biol Chem 269:32572–32578 Tan RS, Taniguchi T, Harada H (1996) Identification of the lysyl oxidase gene as target of the antioncogenic transcription factor, IRF-1, and its possible role in tumor suppression. Cancer Res

56:2417–2421

Trackman PC, Pratt AM, Wolanski A, Tang SS, Offner GD, Troxler RF, Kagan HM (1990) Cloning of rat aorta lysyl oxidase cDNA:

complete codons and predicted amino acid sequence. Biochem- istry 29:4863–4870 Trackman PC, Pratt AM, Wolanski A, Tang SS, Offner GD, Troxler RF, Kagan HM (1991) Cloning of rat aorta lysyl oxidase cDNA:

complete codons and predicted amino acid sequence. Biochem- istry 30:8282 Trackman PC, Bedell-Hogan D, Tang J, Kagan HM (1992) Post- translational glycosylation and proteolytic processing of a lysyl oxidase precursor. J Biol Chem 267:8666–8671

Lysyl oxidase: a potential target for cancer therapy

Trackman PC, Graham RJ, Bittner HK, Carnes DL, Gilles JA, Graves DT (1998) Inflammation-associated lysyl oxidase protein expres- sion in vivo, and modulation by FGF-2 plus IGF-1. Histochem Cell Biol 110:9–14 Tsuchiya MI, Okuda H, Takaki Y, Baba M, Hirai SI, Ohno S, Shuin T (2005) Renal cell carcinoma- and pheochro-mocytoma-specific altered gene expression profiles in VHL mutant clones. Oncol Rep 13:1033–1041 Urashima T, Zhao M, Wagner R, Fajardo G, Farahani S, Quertermous T, Bernstein D (2008) Molecular and physiological character- ization of RV remodeling in a murine model of pulmonary stenosis. Am J Physiol Heart Circ Physiol 295(3):H1351–H1368 Uzel MI, Shih SD, Gross H, Kessler E, Gerstenfeld LC, Trackman PC (2000) Molecular events that contribute to lysyl oxidase enzyme activity and insoluble collagen accumulation in osteosarcoma cell clones. J Bone Miner Res 15:1189–1197 Uzel MI, Scott IC, Babakhanlou-Chase H, Palamakumbura AH, Pappano WN, Hong HH, Greenspan DS, Trackman PC (2001) Multiple bone morphogenetic protein 1-related mammalian metalloproteinases process pro-lysyl oxidase at the correct physiological site and control lysyl oxidase activation in mouse embryo fibroblast cultures. J Biol Chem 276:22537–22543 Vlodavsky I, Friedmann Y (2001) Molecular properties and involve- ment of heparanase in cancer metastasis and angiogenesis. J Clin Invest 108:341–347 Vrhovski B, Weiss AS (1998) Biochemistry of tropoelastin. Eur J Biochem 258:1–18

Wakasaki H, Ooshima A (1990) Immunohistochemical localization of lysyl oxidase with monoclonal antibodies. Lab Invest

63:377–384

Watanabe T, Ichihara M, Hashimoto M, Shimono K, Shimoyama Y, Nagasaka T, Murakumo Y, Murakami H, Sugiura H, Iwata H, Ishiguro N, Takahashi M (2002) Characterization of gene expression induced by RET with MEN2A or MEN2B mutation. Am J Pathol 161(1):249–256 Wolf C (2010) Lysyl oxidase-like 1 gene polymorphisms in german patients with normal tension glaucoma, pigmentary glaucoma and exfoliation glaucoma. J Glaucoma 19(2):136–141 Wu Y, Rich CB, Lincecum J, Trackman PC, Kagan HM, Foster JA (1992) Characterization and developmental expression of chick aortic lysyl oxidase. J Biol Chem 267:24199–24206 Wu M, Min C, Wang X, Yu Z, Kirsch KH, Trackman PC, Sonenshein GE (2007) Repression of BCL2 by the tumor suppressor activity of the lysyl oxidase propeptide inhibits transformed phenotype of lung and pancreatic cancer cells. Cancer Res 67(13):6278–6285 Yeowell HN, Marshall MK, Walker LC, Ha V, Pinnell SR (1994) Regulation of lysyl oxidase mRNA in dermal fibroblasts from normal donors and patients with inherited connective tissue disorders. Arch Biochem Biophys 308:299–305 Zhou Y, Wang X, Jiang L, Tan R, Xiong M, He W, Fang Li, Wen P, Yang J (2010) Uric acid increases fibronectin synthesis through upregulation of lysyl oxidase expression in rat renal tubular epithelial cells. Am J Physiol Renal Physiol 299:F336–F346

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