Warburg Effect

Anirudh Kannan
23rd Feb 2016

Agenda
Introduction
2) Oxidative phosphoryltion & Glycolysis
3) Why cancer cells activate glycolysis in
the presence of O2
1)

4)

How cancer cells activate glycolysis in

the presence of O2

5)

Drugs used for treatment of cancer

About Otto Heinrich

Warburg

German Physiologist, Nobel Laureate

and medical doctor
Served as Uhlan in army (WW1),
awarded Iron Cross for bravery
Sole Laureate of Nobel Prize in
physiology in 1931 (Nicotinamide,
enzymes involved in fermentation and
discovery of flavin)
Nominated 47 times
Studied metabolism of tumours

Introduction
Cells

obtain energy in 2 ways

1. oxygen dependent oxidative
phosphorylation (OXPHOS)
2. oxygen independent glycolysis
.Pasteur effect Presence of O2
activates OXPHOS, inhibits glycolysis
.Warburg effect Cancer cells activate
glycolysis in presence of O2
.Persistent

activation of aerobic
glycolysis leads to cancer
development

OXPHOS and Glycolysis

OXPHOS and Glycolysis

OXPHOS

Couples oxidation of NADH and

FADH2 with phosphorylation of ADP
to form ATP
Electrons provided by oxidation need
to be accepted by oxygen, so oxygen
dependent
Glycolysis

1 glucose -> 2 pyruvate + ATP

NAD+ consumed, regenerated by
conversion of pyruvate to lactate

Comparison
OXPHOS

Glycolysis

Oxygen Dependent

Oxygen independent

More efficient Oxidation

of one molecule of Glucose
yields 30 ATPs

Oxidation of one Glucose

yields only 2 ATPs

Yield of ATP is slow

Faster Yield of ATP is

much faster

Pasteur

observed ATP production moved

from OXPHOS to Glycolysis in low O2
conditions
Otto Warburg discovered glycolysis takes
place in adequate amounts of O2 aerobic
glycolysis Called Warburg Effect

Two Puzzling Questions

WHY: If OXPHOS is more effective in

generating ATP when compared to

glycolysis, why do cancer cells activate
glycolysis when oxygen levels are
adequate?
HOW: If oxygen acts as glycolysis

inhibitor, how do cancer cells still

manage to undergo glycolysis?

WHY? Activation of Glycolysis in O2

Warburg

proposed that it may be due

to Irreversible damage to OXPHOS
Inactivation of p53, most commonly
mutated gene in cancer, inhibits
cytochrome c oxidase activity in OXPHOS
(e- transfer to O2)

But

Warburg effect has also been

observed in non-transformed
proliferating cells (non-malignant
tumors)
Does not support irreversible damage to
OXPHOS

Other Reasons for Glycolysis

activation
Persistent

activation of glycolysis leads to

environmental acidosis growth
advantage to cancer cells toxic to
normal, harmless to cancer
Glycolysis also helps with building the
Carbon skeleton needed for biosynthesis
Which is essential for uncontrolled
proliferation, Cancer
If

Glucose supply is not limited, Glycolysis

produced ATP much faster than OXPHOS
Satisfies the Enormous demand of Growing
cells for ATP

Glycolysis Carbon Skeleton

How? Activation of Glycolysis in O2

Alteration in O2 mechanism
dysoxia or dysoxic metabolism
(low O2)

O2 -> H2O OXPHOS

O2 -> O2- -> H2O2 -> H2O

This activates Aerobic

Glycolysis (Warburg Effect)

O2- produces intracellular

alkalinization (pHi,) which
increases Phosphofructokinase
(PFK) activity, which increases
glycolysis
H2O2 increases HIF-1 activity,
which transcribes genes
responsible for glucose
transporters & glycolytic
enzymes which are essential

O2- ROS Superoxide Anion

Experimental
Observations

Warburg

proposed irreversible damage to

OXPHOS, while non-malignant tissues
also show Warburg effect
This can be explained by the Proposed model,
which attributes inhibition to increased ATP
rather than O2

Cancer

cells have increased rate of

Glycolysis due to adaptation to
intermittent hypoxia
Intermittent hypoxia increases O2- generation,
which supports Glycolysis
O2- increases intracellular alkalinization, which
inhibits p53 leading to increased Glycolysis

HIF-1 also inhibits

OXPHOS

Glycolysis Inhibition: Strategies

& Drugs
Reducing

Blood and interstitial glucose

by Insulin Therapy
Inhibition of Hexokinase (HK) which
mediates the first & rate limiting reaction
in Glycolysis
Drug: Lonidamine, derivative of indazole-3carboxilic acid
Drug: pyruvate analog 3-bromopyruvate
Drug: imatinib, already approved for clinical
use
Inhibitor

for reduced pH (which reduces

PFK activity)
Drug: 5-5 Dimethyl Ameloride (DMA)

 Inhibition

of HIF-1 activity reduces activation

of aerobic glycolysis
i.
Drugs: topotecan, imatinib, NS398,
ibuprofen
ii. Antioxidants like catalase
. Oxamate (analogue of pyruvate) blocks
conversion of pyruvate to lactate
. Iodoacetate inhibits glyceraldehyde-3-P
activity
. Enolase catalyses the conversion of 2phosphoglycerate to phosphoenolpyruvate
. Aldolase catalyses the reversible
conversion of fructose-1,6-bisphosphate to

REFERENCES
The

Warburg Effect: Why and How do cancer

cells activate glycolysis in the presence of
oxygen?
http://www.ncbi.nlm.nih.gov/pmc/articles/PM
C2849637/
http://science.sciencemag.org/content/324/5
930/1029
https://www.researchgate.net/post/What_is_
meant_by_the_Warburg_effect

THANK YOU