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04.2 kurland pc

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04.2 kurland pc

  1. 1. Warburg Effect : Bioenergetics and the metabolicrequirements of cell proliferation<br />Irwin J. Kurland MD PhD<br />Associate Professor, Endocrinology<br />Director, Metabolomics Facility<br />Albert Einstein College of Medicine<br />
  2. 2. Background<br />Most cancer cells rely on aerobic glycolysis, a phenomenon termed “the Warburg effect”<br />Aerobic glycolysis is an inefficient way to generate ATP<br />The metabolism of cancer cells (the “Warburg effect”), is adapted to facilitate the uptake and incorporation of nutrients into the biomass (e.g., nucleotides, amino acids, and lipids) needed to produce a new cell<br />
  3. 3. Warburg bioenergetics-Inefficient ATP production is a problem only when resources are scarce<br />Vander Heiden, Cantley, Thompson: Science 2009<br />
  4. 4. Practicalities<br />Can understanding the Warburg effect yield a way of “fingerprinting”/staging tumors, at least with regard to capacity for invasiveness and proliferation ?<br />Can understanding the Warburg effect lead to a way of designing combination therapy against cancer using metabolic inhibitors ?<br />
  5. 5. Signaling/metabolic interactions in cancer cells pertinent to the Warburg effect<br />Vander Heiden, Cantley, Thompson: Science 2009<br />
  6. 6. Practicalities<br />Can understanding the Warburg effect yield a way of “fingerprinting”/staging tumors, at least with regard to capacity for invasiveness and proliferation ?<br />Can understanding the Warburg effect lead to a way of designing combination therapy against cancer using metabolic inhibitors ?<br />
  7. 7. “Fingerprinting” tumors:Metabolomic profile associated with transformation/ invasiveness and proliferation<br />Lu, Bennet, Mu,Rabinowitz and Kang: JBC March 2010<br />
  8. 8. Lu, Bennet, Mu,Rabinowitz and Kang: JBC March 2010<br />
  9. 9. Redox state and tumorgenesis<br />.<br />Lu, Bennet, Mu,Rabinowitz and Kang: JBC March 2010<br />
  10. 10. A two-step metabolic progression hypothesis during mammary tumor progression<br />The first step accompanies the acquisition of tumorigenicity:<br />Includes altered glycolysis, pentose phosphate pathway (PPP), and fatty acid synthesis, as well as decreased GSH/GSSG redox pool<br /> the second step is correlated with the gain of the general metastatic ability and includes further changes in glycolysis and tricarboxylic acid cycle (TCA cycle), further depletion of the glutathione species, and increased nucleotides.<br />
  11. 11. Designing anti-metabolite therapies in the context of the Warburg Effect<br /> Shut down metabolic pathways involved in biomass production for highly proliferative cells<br />Interfere with lactate-based metabolic symbiosis in tumors-> disrupt the metabolic symbosis between a oxygenated tumor shell layer and the deeper hypoxic layers<br /> Interfere with lactate-based cancer associated fibroblasts-tumor cell symbiosis<br />
  12. 12. Warburg-Pathways<br />6<br />16<br />7-AICAR<br />17<br />1<br />8<br />3<br />18<br />10<br />4<br />15<br />
  13. 13. 7.45<br />160<br />7.40<br />150<br />The bio-cartridge is raised, bringing the system back to baseline<br />The bio-cartridge is raised, bringing the system back to baseline<br />The bio-cartridge is raised, bringing the system back to baseline<br />pH (ECAR)<br />OCR<br />7.35<br />140<br />mm O2 (OCR)<br />7.30<br />130<br />ECAR<br />7.25<br />120<br />7.20<br />100<br />1<br />2<br />3<br />4<br />5<br />6<br />7<br />Time (min)<br />Measuring Oxygen Consumption Rate (OCR) and Extracellular Acidification Rate (ECAR)<br />C2<br />C2<br />C2<br />C2<br />C2<br />C2<br />C2<br />C2<br />C2<br />C2<br />C2<br />C2<br />C2<br />C2<br />C2<br />C2<br />C2<br />C2<br />C2<br />C2<br />C2<br />C2<br />C2<br />C2<br />C2<br />C2<br />C2<br />C2<br />C2<br />C2<br />C2<br />C2<br />C2<br />C2<br />A temporary 3µl micro-chamber is formed<br />C2<br />C2<br />C2<br />C2<br />C2<br />C2<br />C2<br />C2<br />C2<br />C2<br />C2<br />C2<br />C2<br />C2<br />C2<br />C2<br />C2<br />C2<br />C2<br />C2<br />C2<br />C2<br />Well 1<br />Well 2<br />
  14. 14.
  15. 15. Knockdown of LDH-A in mouse mammary tumor cells<br />Fantin et al Cancer Cell 2006<br />
  16. 16. Reducing LDH-A increases dependence of cell on mitochondrial respiration<br />Fantin et al Cancer Cell 2006<br />
  17. 17. 2-DG therapy: Human Osteosarcoma Cells in Nude Mice<br />Maschek et al Cancer Research 2004<br />
  18. 18. Designing anti-metabolite therapies in the context of the Warburg Effect<br /> Shut down metabolic pathways involved in biomass production for highly proliferative cells<br />Interfere with lactate-based metabolic symbiosis in tumors-> disrupt the metabolic symbosis between a oxygenated tumor shell layer and the deeper hypoxic layers<br /> Interfere with lactate-based cancer associated fibroblasts-tumor cell symbiosis<br />
  19. 19. Therapeutic targeting of lactate-based metabolic symbiosis in tumors<br />Sonveaux et al JCI 2008, MCT = monocarboxylate transporter<br />
  20. 20. Loss of Cav-1 in fibroblasts is a marker of theWarburg effect in the mammary cancer-associatedstroma<br />Pavlides et al Cell Cycle 2009<br />
  21. 21. Cells in a multicellular organismthat are not stimulated to proliferate rely primarily on oxidative metabolism<br />

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