The Warburg Effect: Role in Cancer Paul Bansal, Robert Calvaruso, Hemangi Dave & Henry Pun Sept 29. 2015 M142 Fall 2015 structor: Dr. Jeffrey Henderson
Jan 29, 2016
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
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
• 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 shows it as a byproduct of cancer
• Initial explanation for Warburg effect - dysfunction of mitochondrial cells
http://www.nobelprize.org/nobel_prizes/medicine/laureates/1931/
What is the Warburg Effect?
• 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
http://nutritionaloncology.org/cancerCellMetabolism.html
Kelloff (2005)
Bensinger (2012)
• Non-invasive assay for visualizing rate of glucose uptake in cell
• Uses radiotracer: 2-deoxy-2[18F]fluoro-D-glucose (fluorodeoxyglucose)
• Approved for diagnosis and monitoring in many cancers
• Not useful for some cancers (prostate, pancreatic, hepatocellular carcinoma)• No Warburg effect• Poor probe perfusion into tumour• Low tumour cell density• High background• High G6P expression
FDG-PET as a monitoring tool for anticancer therapy
Vander Heiden (2009)
Therapeutics
Pelicano (2006)
Drug Therapy
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
• Therapeutics that exploit the Warburg effect
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
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:
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
Multiple causes PKM2 isoform switching Overexpression of HIF1, Myc P53 underexpression
Detected using FDG-PET 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
Therapeutic applications 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
Pelicano (2006)
Summary
References Cancer cell metabolism. (2008). Retrieved from http://nutritionaloncology.org/cancerCellMetabolism.html
Davidescu, M. et al. (2015). “The energy blockers bromopyruvate and lonidamin lead GL15 glioblastoma cells to death by different p53-dependent routes.” Nature: Scientific Reports. 5:14343, p. 1-12.
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.
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.
Heiden, M.G.V. et al. (2009). “Understanding the Warburg effect: the metabolic requirements of cell proliferation” Science. 324(5930): 1029-1033.
Kim J. and Dang C. (2006) Cancer’s Molecular Sweet Tooth and the Warburg Effect. Cancer Res. 66:8927-8929.
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.
Hsu P.P. and Sabatini D.M. (2008). “Cancer Cell Metabolism: Warburg and Beyond.” Cell. 134:703-707.
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.
Pelicano H. et al. (2006). “Glycolysis inhibition for anticancer treatment.” Oncogene. 25:4633-4646.
Ko Y.H. et al (2004). “Advanced cancers: eradication in all cases using 3-bromopyruvate therapy to deplete ATP. Biochem Biophys Res Commun. 324(1)269-75.
Vidugiriene J. (2013) “Tools for cell metabolism: Bioluminescent NAD(P)/NAD(P)H-Glo Assays”. Promega Corp.
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?