3. ENERGY for Cells
Mitochondria
Oxygen dependent Process
Oxidative phosphorylation
ALSO
Glycolysis
Does not require oxygen
Cytoplasm
36 ATP 2 ATP
More efficient
4. Adequate oxygen
ATP is generated
by
Oxidative
Phosphoryation
As Oxygen
Decreases
Shift from
Oxidative
phosphorylation
to Glycolysis
PASTEUR EFFECT
Anaerobic glycolysis
5. Otto Heinrich
Warburg
Early 20th Century
German Physiologist
Observed that cancer cells had
increased rates of glycolysis
Despite the availability of adequate
oxygen levels
Aerobic glycolysis
WARBURG EFFECT
9. The puzzling questions
Why do cancer cells activate glycolysis despite the
presence of oxygen?
How do they manage to activate glycolysis despite
the presence of oxygen?
Is this phenomenon Cancer specific?
11. No!
This is evident in rapidly growing normal tissues too as
in embryonic tissue
It is a property of growing cells but got “stuck” in
cancer cells!!
12. Why do cancer cells activate glycolysis despite the
presence of oxygen?
Assures ATP synthesis when tumor outgrows its oxygen supply
The metabolic intermediates of AEROBIC GLYCOLYSIS provides
raw material for the synthesis of cellular components in these
rapidly dividing tumor cells! And also favor tumor growth
Release of acid lowers extracellular pH which favors tumor
invasion and suppresses immune effectors
13. How do they manage to activate glycolysis despite
the presence of oxygen?
14. Overexpression of Hypoxia
inducible factor 1 ( HIF 1)
Increases transcription of
many genes
Codes proteins favoring
cancer
Glucose
metabolism
Apoptosis
resistance
Angiogenesis
15. • HIF-1 increases glucose uptake by
upregulating GLUT1 expression.
• HIF-1 increases glucose phosphorylation by
upregulating hexokinase 2 expression
• Increase in HIF-1 has similar effect as loss of
p53 function( results in greater glycolytic flux,
reduced pyruvate oxidation, and reduced
production of ATP by oxidative
phosphorylation)
Glucose
16. How do they manage to activate glycolysis
despite the presence of oxygen?
• Induction of glycolytic enzymes BY overexpression of HIF 1
• Induction of Pyruvate dehydrogenase kinase
• Down regulation of mitochondrial enzymes and decrease in the
number of mitochondria
• Mitochondrial defects due to mutations in mitochondrial DNA leading
to malfunction of oxidative phosphorylation
18. Diagnostic Therapeutic
This property of “glucose
hunger” is used in PET
scanning of solid tumors
18F-flourodeoxyglucose, a
nonmetabolizable glucose
derivative of glucose is used
where this is preferentially
taken by tumor cells/rapidly
dividing cells
Numerous Glycolytic
inhibitors have been
developed which can be
potential anticancer
drugs
19. Viewpoint!
• Warburg effect is a growth promoting metabolic alteration in cancer
cells
• One of the Hallmarks of Cancer!
• lots of explanations are given for this effect.
• However the exact cause and its value,.. As of now still remains
elusive!