Transcript Is the difference important for growth and survival of

The Hallmarks of Cancer: old version
The Hallmarks of Cancer: emerging new
entries
The Hallmarks of Cancer: new version
Metabolism and Cancer
1.
2.
3.
4.
Define and explain the Pasteur effect.
Define and explain the Warburg effect.
Define aerobic glycolysis.
Give a biochemical explanation for why cancer
cells accumulate greater amounts 18Ffluorodeoxyglucose than normal cells.
5. Explain why the Warburg hypothesis for cancer is
not considered correct.
Metabolism and Cancer
Objectives
6. how the metabolism of glucose in cancer cells
differs from normal cells.
8. how the metabolism of glutamine in cancer cells
differs from normal cells.
9. What purpose does altered metabolism serve in
cancer cells?
10. Promotion of ROS production/decrease of ROS
removal.
Metabolism and Cancer
Objectives
12. Illustrate how mitochondria are involved in ROS
production.
13. Explain why uncouplers of oxidative
phosphorylation decrease ROS production.
14. Discuss whether the difference in metabolism is
important for growth and survival of cancer cells.
15. Explain whether you think the metabolic
difference between normal cells and cancer cells
has therapeutic potential.
Normal cell metabolism
• Tight coupling of glucose to pyruvate and
pyruvate to CO2 and H2O
Glucose
2 Pyruvate
2 Lactate
O2
6 CO2
Normal cell metabolism
• Tight coupling of glucose to pyruvate and
of pyruvate to CO2 and H2O
Glucose
2 Pyruvate
2 Lactate
•Effect of Lack of O2
6 CO2
Normal cell metabolism
• Louis Pasteur: 1822-1895
– Rates of fermentation are high
anaerobically but low aerobically
• Pasteur effect: inhibition of fermentation
by oxygen,
• Glucose
2 pyruvate
2 lactate
•consumption of oxygen inversely correlated to glucose one
Cancer Cell Metabolism
• Defective coupling of glucose to pyruvate
and pyruvate to CO2 and H2O
• Cancer cells produce large amounts of
lactate in the presence of oxygen
• Pasteur effect is defective in cancer
cells
Metabolism and Cancer
• Otto Warburg: 1883-1970
– Warburg effect: “Aerobic glycolysis”:
generation of lactate in the presence of
oxygen
Glucose
2 pyruvate
O2
6 CO2
2 lactate
• Effect of lack of O2
• “Dysfunctional mitochondria likely responsible”
Is aerobic glycolysis an in vitro artifact?
Positron emission
tomography
18F-fluorodeoxyglucose
Vander Heiden
et al. Science
2009; 329: 1029
Metabolism and Cancer
• Otto Warburg:1930.
– recognized Pasteur effect is defective in cancer
– discovered cancer cells carry out aerobic glycolysis
(Warburg effect)
– suggested “deficiencies in mitochondrial oxidative
metabolism is responsible”.
– proposed “replacement of respiration by
fermentation is the primary cause of malignant cell
transformation” (Warburg hypothesis)
– suggested “altered metabolism of cancer cells might
provide a means to treat cancer”
Metabolism and Cancer
• The Warburg hypothesis (replacement of
respiration by fermentation is the primary
cause of cancer) is not correct
• Cancer is caused by mutations that:
– inactivate tumor suppressor genes
– activate proto-oncogenes
– (and many others…..)
Why altered metabolism in cancer?
• Warburg was wrong about what causes cancer –
but he discovered an intrinsic difference in
metabolism between cancer cells and normal cells
• Are there other metabolic differences between
normal and cancer cells?
• Is the difference important for growth and survival
of cancer cells?
• Does the difference in metabolism between normal
and cancer cells have therapeutic potential?
Metabolism and Cancer
• The metabolism of glucose and glutamine by
normal cells is very efficient. Primary end products
are CO2, H2O, and ammonia (or urea). Maximum
ATP yield per mole of glucose and glutamine is
achieved.
• The metabolism of glucose and glutamine by
cancer cells is very wasteful. Primary end products
are CO2, H2O, lactate, pyruvate, alanine, and
aspartate. Maximum ATP yield per mole of glucose
and glutamine is not achieved (incomplete
metabolism).
What purpose does altered
metabolism serve in cancer cells?
• Assures ATP synthesis when tumor outgrows its oxygen
supply
• Assures supply of building blocks for proliferation and
growth
• Creates space by starving neighboring cells for nutrients
• Release of acid lowers extracellular which favors tumor
invasion and suppresses immune effectors
• Increases resistance to oxidative stress by promoting
NADPH production and reduction of glutathione
• Reduces production of reactive oxygen species (ROS) by
mitochondria
Can normal cell metabolism cause
cancer?
• Normal metabolism produces reactive
oxygen species (ROS)
• ROS can induce cancer
Reactive oxygen species and cancer
• The good things about ROS
– Second messenger in signal transduction
– Kills bacteria that invade cells
– Induces senescence and apoptosis
• The bad thing about ROS
– High concentrations react with DNA
What increases ROS production and
oxidative damage?
•
•
•
•
Smoking
Chemicals (carcinogens)
UV radiation
Over eating
What affects ROS?
• Uncoupling of oxidative phosphorylation
• Enzymes that destroy superoxide radicals
and hydrogen peroxide
• Caloric restriction
• Warburg effect
PPP AND Warburg
metabolism
reversible inactivation of PKM2 by oxidation of Cys358, The low catalytic rate of
PKM2 reduces flux through glycolysis, increasing the flux through the PPP and
generating NADPH to quench oxidative stress. .
Multiple changes in gene expression
are responsible for aerobic glycolysis
in cancer cells
• Inactivation of p53
• Activation of HIF-1
How “aerobic” glycolysis is increased
in cancer cells
• Hypoxia induces HIF-1 which induces expression of
glycolytic enzymes.
• Tumor suppressor p53, which normally maintains
low concentration of F2,6P2 (activator of PFK1), is
down regulated in cancer cells.
• HIF-1 induces expression of PDK1 which inhibits
the pyruvate dehydrogenase complex, which
inhibits pyruvate oxidation.
p53 reduces “aerobic” glycolysis
• p53 promotes transcription of TIGAR, a phosphatase,
that hydrolyzes F2,6P2, a positive effector of PFK1.
• p53 promotes expression of the thiamine transporter.
Greater uptake of thiamine increases cellular [TPP],
which increases activities of the pyruvate
dehydrogenase and -ketoglutarate dehydrogenase
complexes.
• p53 increases activity of the cytochrome oxidase.
Greater cytochrome oxidase promotes ATP
production. Greater cellular ATP suppresses
glycolysis at PFK1.
p53 and Cancer
• Mutations in the p53 gene is the most common
cause of cancer.
• Loss of p53 function in cancer cells causes greater
glycolytic flux, reduced pyruvate oxidation, and
reduced production of ATP by oxidative
phosphorylation.
HIF-1 increases “aerobic” glycolysis
• HIF-1 increases glucose uptake by up regulating
GLUT1 expression.
• HIF-1 increases glucose phosphorylation by up
regulating hexokinase 2 expression.
• HIF-1 increases flux through PFK-1 by up regulating
expression of the “hypoxia-inducible 6-PF-2-K/F-2,6P2ase”, a form of this bifunctional enzyme in which the
kinase moiety is activated by AMPK.
HIF-1 increases
“aerobic” glycolysis
CA9
H+
• HIF-1 up regulates expression of pyruvate kinase M2,
aldolase A, enolase 1, and carbonic anhydrase IX.
• HIF-1 up regulates LDHA and the lactate transporter MCT4.
• HIF-1 up regulates expression of PDK1 and PDK3.
HIF-1, p53 and Cancer
• HIF-1 is activated in many cancers.
• Increase in HIF-1 induces the same effects as loss
of p53 function, i.e. causes greater glycolytic flux,
reduced pyruvate oxidation, and reduced
production of ATP by oxidative phosphorylation.
• Therefore, because of increase in HIF-1 and
decrease in p53, many tumors use “aerobic”
glycolysis as their major energy pathway.
SIRT3 and metabolic control
SIRT3, ROS
and HIF1….
1. SIRT3 is a NAD-dependent deacetylase, deleted in many human
cancers, which activates SOD
2. Lack of SIRT3 inhibits deacetylation/ activation of SOD. Acetylated
SOD is inactive, causing an increase in O2•3. ROS leads to PDH oxidation/inactivation
4. HIF-1 is stabilized and activates the Warburg metabolism
Glutamine metabolism also differs
between normal and cancer cells
Cancer cells and acidity
Tumor metabolism
The microsymbiosys within cancer mass
Sonvenaux, P, J Clin Invest. 2008
Upon MCT1 inhibition, oxidative tumor cells switch
from lactate oxidation to glycolysis, preventing
glucose delivery to hypoxic/glycolytic
cells, which die from glucose starvation
Tumor-stroma
interactions
THE “REVERSE WARBURG EFFECT”
PROSTATE CARCINOMA UNDERGOES SIMILAR REVERSE WARBURG EFFECT UPON
CONTACT WITH THEIR STROMAL FIBROBLASTS
Does the metabolic difference have therapeutic
potential?
Inhibitors of:
• Hexokinase
• Pyruvate kinase
• LDH-A
• Monocarboxylate
translocase (MCT)
• Pyruvate dehydrogenase
kinase
• Glutaminase
Vander Heiden et al. Science 2009; 329: 1029