The Warburg Effect:
Role in Cancer
Paul Bansal, Robert Calvaruso, Hemangi Dave & Henry Pun
Sept 29. 2015
PHM142 Fall 2015
Instructor: Dr. Jeffrey Henderson
Overview
 Discovery
& Description of the Warburg Effect
 Mechanism
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Glycolysis pathway
NADPH/ROS
Occurs in aerobic conditions (Warburg effect = aerobic glycolysis)
 Detection
 FDG-PET
 Therapeutics
 Drugs that target specifically target glycolytic pathway to selectively
dest
The Discovery of the Warburg Effect
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Cellular phenomenon in cancer cells discovered by Otto Warburg
in 1924
 Initially measured lactate production and glucose consumption
in rat liver carcinoma and normal liver tissue
 Warburg determined that cancer tissue consumed 10x more
glucose than accounted for by respiration, and produced up to
100X more lactic acid than in normal tissue
Cancerous cells preferentially use glycolysis for energy production
rather than oxidative phosphorylation
Initially believed to be the cause of cancer but recent evidence http://www.nobelprize.org/nobel_prizes/
medicine/laureates/1931/
shows it as a byproduct of cancer
Initial explanation for Warburg effect - dysfunction of
mitochondrial cells
What is the Warburg Effect?
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Utilization of aerobic
glycolysis as the major source
of ATP
Activates pentose phosphate
cycle
• Produces NADPH
• Protects cells against ROS
Involves massive increase in
glucose uptake, reliance on
glycolysis, and inhibition of
oxidative phosphorylation
Vidugiriene (2013)
What factors push cells to enter aerobic glycolysis?
1) Genomic regulation
 Phosphoglycerate dehydrogenase (PHGDH)
2) Transcriptional regulation
 HIF1
 MYC
 P53
3) Metabolic isoform switching
 Pyruvate kinase M2 (PKM2)
 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB)
4) Post-translational regulation
 Activation of PI3K/AKT pathway signaling
 PKM2
Many factors promote Warburg Effect
Bensinger (2012)
Vander Heiden (2009)
Detection using FDG-PET
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Non-invasive assay for visualizing rate of
glucose uptake in cell
Uses radiotracer: 2-deoxy-2[18F]fluoro-Dglucose (fluorodeoxyglucose)
Approved for diagnosis and monitoring in
many cancers
Not useful for some cancers (prostate,
pancreatic, hepatocellular carcinoma)
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Kelloff (2005)
No Warburg effect
Poor probe perfusion into tumour
Low tumour cell density
High background
High G6P expression
Bensinger (2012)
http://nutritionaloncology.org/cancerCellMetabolism.html
FDG-PET as a monitoring tool for anticancer therapy
Vander Heiden (2009)
Therapeutics
Pelicano (2006)
Drug Therapy
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Therapeutics that exploit the Warburg effect
Compound status
Mechanisms of action
Drug development
2-Deoxyglucose
Inhibits phosphorylation of glucose by hexokinase
Clinical trials (I/II)
Lonidamine
Inhibits glycolysis and mitochondrial respiration
Clinical trials (II/III)
Inhibits HK; dis-associating HK from mitochondria
3-Bromopyruvate
Inhibits HK; acts as an alkylating agent
Pre-clinical
Imatinib
Inhibit Bcr-Abl tyrosine kinase; causes a decrease in HK and G6PD activity
Approved for clinical use
Oxythiamine
Suppresses PPP by inhibiting transketolase; inhibits pyruvate dehydrogenase
Pre-clinical
Pelicano (2006)
3-BrPA use in-vivo
Ko (2004)
Lonidamine (LND) in tumorigenic GL15 cells
Davidescu (2015)
Oxythiamine in mice lung carcinoma
Yang (2010)
Summary
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The Warburg effect was discovered in 1924 by Otto Warburg
The Warburg effect is the reliance of cancer cells on aerobic glycolysis as opposed to oxidative
phosphorylation
Features:
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ATP generation via glycolysis
Increased NADPH through the pentose phosphate shunt
Generates protection against reactive oxidative species – allows continuous cell proliferation
Promotes generation of macromolecules required for proliferation
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PKM2 isoform switching
Overexpression of HIF1, Myc
P53 underexpression
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Uses radiolabelled glucose analog (FDG) to visualize areas of increased glucose uptake
Can detect location of tumours as well as monitor the progression of cancer therapy
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Drugs (ex. 3-BrPA, 2-DG, oxythiamine) target enzymes at various points in the glycolytic pathway
Thereby selectively inhibiting cancer cell proliferation
Drug examples: 3-BrPA, 2-DG, oxythiamine target various
Multiple causes
Detected using FDG-PET
Therapeutic applications
Summary
Pelicano (2006)
References
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Cancer cell metabolism. (2008). Retrieved from http://nutritionaloncology.org/cancerCellMetabolism.html
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Davidescu, M. et al. (2015). “The energy blockers bromopyruvate and lonidamin lead GL15 glioblastoma cells to death by different p53dependent routes.” Nature: Scientific Reports. 5:14343, p. 1-12.
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Pedersen, P.L. (2007). “Warburg, me and Hexokinase 2: Multiple discoveries of key molecular events underlying one of cancers’ most
common phenotypes, the “Warburg Effect”, i.e., elevated glycolysis in the presence of oxygen”. Journal of Bioenergy and Biomembranes.
39: 211-222.
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Yang, CM et al. (2010). “The in vitro and in vivo anti-metastatic efficacy of oxythiamine and the possible mechanisms of action.” Clinical
Experimental Metastasis. 27: 341-349.
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Heiden, M.G.V. et al. (2009). “Understanding the Warburg effect: the metabolic requirements of cell proliferation” Science. 324(5930):
1029-1033.
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Kim J. and Dang C. (2006) Cancer’s Molecular Sweet Tooth and the Warburg Effect. Cancer Res. 66:8927-8929.
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Bensinger S.J. and Christofk H.R. (2012). “New aspects of the Warburg effect in cancer cell biology.” Seminars in Cell & Developmental
Biology. 23:352-361.
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Hsu P.P. and Sabatini D.M. (2008). “Cancer Cell Metabolism: Warburg and Beyond.” Cell. 134:703-707.
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Kelloff G.J. et al. (2005). “Progress and Promist of FDG-PET Imaging for Cancer Patient Management and Oncologic Drug Development.” Clin
Cancer Res. 11(8):2785-2808.
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Pelicano H. et al. (2006). “Glycolysis inhibition for anticancer treatment.” Oncogene. 25:4633-4646.
Mechanism
Glycolysis generates 2 ATP, while oxidative phosphorylation generates 36-38ATP. Despite that, most cancer
cells have been found to exclusively produce their energy via the glycolytic pathway regardless of the level of
oxygen in the surroundings. A possible reason for this is that the glycolytic pathway enables the production of
specific metabolites (NADPH) that decrease the presence of ROS species/oxidative stress. This is crucial for
tumour cells as it allows them to proliferate indefinitely and survive in “unfavourable conditions: NADPH -- how?