Warburg effect

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The phrase "Warburg effect" (/vrbr/) is used for two unrelated observations in biochemistry, one in plant
physiology and the other in oncology, both due to Nobel laureate Otto Heinrich Warburg.
Contents
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1Plant physiology

2Oncology
o

2.1Basis

2.2Possible explanations

2.3Glycolytic inhibitors

2.4Blood glucose levels

3Alternative models

4Cancer metabolism and epigenetics

5References

Plant physiology[edit]
In plant physiology, the Warburg's effect is the decrease in the rate of photosynthesis by
high oxygen concentrations.[1][2] Oxygen is a competitive inhibitor of the carbon dioxidefixation by RuBisCO which
initiates photosynthesis. Furthermore, oxygen stimulates photorespiration which reduces photosynthetic output.
These two mechanisms working together are responsible for the Warburg effect. [3]

Oncology[edit]
Basis[edit]
In oncology, the Warburg effect is the observation that most cancer cells predominantly produce energy by a high
rate of glycolysis followed by lactic acid fermentation in the cytosol,[4][5] rather than by a comparatively low rate of
glycolysis followed by oxidation of pyruvate in mitochondria as in most normal cells.[6][7][8] The latter process
is aerobic (uses oxygen). Malignant, rapidly growing tumor cells typically have glycolytic rates up to 200 times higher
than those of their normal tissues of origin; this occurs even if oxygen is plentiful.
Otto Warburg postulated this change in metabolism is the fundamental cause of cancer,[9] a claim now known as
the Warburg hypothesis. Today, mutations in oncogenes and tumor suppressor genes are thought to be responsible
for malignant transformation, and the Warburg effect is considered to be a result of these mutations rather than a
cause.[10][11]

Possible explanations[edit]
The Warburg effect may simply be a consequence of damage to the mitochondria in cancer, or an adaptation to lowoxygen environments within tumors, or a result of cancer genes shutting down the mitochondria because they are
involved in the cell's apoptosis program which would otherwise kill cancerous cells. It may also be an effect
associated with cell proliferation. Since glycolysis provides most of the building blocks required for cell proliferation,
cancer cells (and normal proliferating cells) have been proposed to need to activate glycolysis, despite the presence
of oxygen, to proliferate.[12] Evidence attributes some of the high aerobic glycolytic rates to an overexpressed form of
mitochondrially-bound hexokinase[13] responsible for driving the high glycolytic activity. In kidney cancer, this effect

could be due to the presence of mutations in the von HippelLindau tumor suppressor gene upregulating glycolytic
enzymes, including the M2 splice isoform of pyruvate kinase. [14]
In March 2008, Lewis C. Cantley and colleagues announced that the tumor M2-PK, a form of the pyruvate
kinase enzyme, gives rise to the Warburg effect. Tumor M2-PK is produced in all rapidly dividing cells, and is
responsible for enabling cancer cells to consume glucose at an accelerated rate; on forcing the cells to switch to
pyruvate kinase's alternative form by inhibiting the production of tumor M2-PK, their growth was curbed. The
researchers acknowledged the fact that the exact chemistry of glucose metabolism was likely to vary across
different forms of cancer; but PKM2 was identified in all of the cancer cells they had tested. This enzyme form is not
usually found in healthy tissue, though it is apparently necessary when cells need to multiply quickly, e.g. in healing
wounds or hematopoiesis.[15][16]

Glycolytic inhibitors[edit]
Many substances have been developed which inhibit glycolysis, and such inhibitors are currently the subject of
intense research as anticancer agents,[17] including SB-204990, 2-deoxy-D-glucose (2DG), 3-bromopyruvate (3BrPA, bromopyruvic acid, or bromopyruvate), 3-BrOP, 5-thioglucose and dichloroacetic acid (DCA). Clinical trials are
ongoing for 2-DG and DCA.[18]
Alpha-cyano-4-hydroxycinnamic acid (ACCA;CHC), a small-molecule inhibitor of monocarboxylate transporters
(MCTs; which prevent lactic acid build up in tumors) has been successfully used as a metabolic target in brain tumor
pre-clinical research.[19][20][21][22] Higher affinity MCT inhibitors have been developed and are currently undergoing
clinical trials by Astra-Zeneca.[23]
Dichloroacetic acid (DCA), a small-molecule inhibitor of mitochondrial pyruvate dehydrogenase kinase,
"downregulates" glycolysis in vitro and in vivo. Researchers at the University of Alberta theorized in 2007 that DCA
might have therapeutic benefits against many types of cancers.[24][25]

Blood glucose levels[edit]

High glucose levels have been shown to accelerate cancer cell proliferation in vitro, while glucose deprivation has
led to apoptosis. These findings have initiated further study of the effects of carbohydrate restriction on tumor
growth. Clinical evidence shows that lower blood glucose levels in late-stage cancer patients have been correlated
with better outcomes.[26]

Alternative models[edit]
A model called the reverse Warburg effect describes cells producing energy by glycolysis, but were not tumor cells,
but stromal fibroblasts. Although the Warburg effect would exist in certain cancer types potentially, it highlighted the
need for a closer look at tumor metabolism.[27][28]
Metabolic reprogramming is also observed in neurodegenerative diseases, Alzheimer's and Parkinson's. This
metabolic alteration is described by the up-regulation of oxidative phosphorylation - called the inverse Warburg
Effect.

Cancer metabolism and epigenetics[edit]

Nutrient utilization is dramatically altered when cells receive signals to proliferate. Characteristic metabolic changes
enable cells to meet the large biosynthetic demands associated with cell growth and division. Changes in ratelimiting glycolytic enzymes redirect metabolism to support growth and proliferation. Metabolic reprogramming in
cancer is largely due to oncogenic activation of signal transduction pathways and transcription factors. Although less
well understood, epigenetic mechanisms also contribute to the regulation of metabolic gene expression in cancer.
Reciprocally, accumulating evidence suggest that metabolic alterations may affect the epigenome. Understanding
the relation between metabolism and epigenetics in cancer cells may open new avenues for anti-cancer strategies.
[29]