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1. Warburg Effect : Bioenergetics and the metabolicrequirements of cell proliferation Irwin J. Kurland MD PhD Associate Professor, Endocrinology Director, Metabolomics Facility Albert Einstein College of Medicine
2. Background Most cancer cells rely on aerobic glycolysis, a phenomenon termed “the Warburg effect” Aerobic glycolysis is an inefficient way to generate ATP 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
4. Practicalities Can understanding the Warburg effect yield a way of “fingerprinting”/staging tumors, at least with regard to capacity for invasiveness and proliferation ? Can understanding the Warburg effect lead to a way of designing combination therapy against cancer using metabolic inhibitors ?
6. Practicalities Can understanding the Warburg effect yield a way of “fingerprinting”/staging tumors, at least with regard to capacity for invasiveness and proliferation ? Can understanding the Warburg effect lead to a way of designing combination therapy against cancer using metabolic inhibitors ?
9. Redox state and tumorgenesis . Lu, Bennet, Mu,Rabinowitz and Kang: JBC March 2010
10. A two-step metabolic progression hypothesis during mammary tumor progression The first step accompanies the acquisition of tumorigenicity: Includes altered glycolysis, pentose phosphate pathway (PPP), and fatty acid synthesis, as well as decreased GSH/GSSG redox pool 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.
11. Designing anti-metabolite therapies in the context of the Warburg Effect Shut down metabolic pathways involved in biomass production for highly proliferative cells Interfere with lactate-based metabolic symbiosis in tumors-> disrupt the metabolic symbosis between a oxygenated tumor shell layer and the deeper hypoxic layers Interfere with lactate-based cancer associated fibroblasts-tumor cell symbiosis
13. 7.45 160 7.40 150 The bio-cartridge is raised, bringing the system back to baseline The bio-cartridge is raised, bringing the system back to baseline The bio-cartridge is raised, bringing the system back to baseline pH (ECAR) OCR 7.35 140 mm O2 (OCR) 7.30 130 ECAR 7.25 120 7.20 100 1 2 3 4 5 6 7 Time (min) Measuring Oxygen Consumption Rate (OCR) and Extracellular Acidification Rate (ECAR) C2 C2 C2 C2 C2 C2 C2 C2 C2 C2 C2 C2 C2 C2 C2 C2 C2 C2 C2 C2 C2 C2 C2 C2 C2 C2 C2 C2 C2 C2 C2 C2 C2 C2 A temporary 3µl micro-chamber is formed C2 C2 C2 C2 C2 C2 C2 C2 C2 C2 C2 C2 C2 C2 C2 C2 C2 C2 C2 C2 C2 C2 Well 1 Well 2
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15. Knockdown of LDH-A in mouse mammary tumor cells Fantin et al Cancer Cell 2006
16. Reducing LDH-A increases dependence of cell on mitochondrial respiration Fantin et al Cancer Cell 2006
17. 2-DG therapy: Human Osteosarcoma Cells in Nude Mice Maschek et al Cancer Research 2004
18. Designing anti-metabolite therapies in the context of the Warburg Effect Shut down metabolic pathways involved in biomass production for highly proliferative cells Interfere with lactate-based metabolic symbiosis in tumors-> disrupt the metabolic symbosis between a oxygenated tumor shell layer and the deeper hypoxic layers Interfere with lactate-based cancer associated fibroblasts-tumor cell symbiosis
19. Therapeutic targeting of lactate-based metabolic symbiosis in tumors Sonveaux et al JCI 2008, MCT = monocarboxylate transporter
20. Loss of Cav-1 in fibroblasts is a marker of theWarburg effect in the mammary cancer-associatedstroma Pavlides et al Cell Cycle 2009
21. Cells in a multicellular organismthat are not stimulated to proliferate rely primarily on oxidative metabolism
Editor's Notes
proliferating mammalian cells, which are exposedto a continual supply of glucose and othernutrients in circulating bloodIt is clear that for a cell to proliferate, the bulkof the glucose cannot be committed to carbon catabolismfor ATP production. In addition, if thiswere the case, the resulting rise in the ATP/ADPratio would severely impair the flux throughglycolytic intermediates, limiting the production ofthe acetyl-CoA and NADPH required for macromolecularsynthesis.synthesis of palmitate, a major constituent of cellularmembranes, requires 7 molecules of ATP, 16 carbonsfrom 8 molecules of acetyl-CoA (coenzymeA), and 28 electrons from 14molecules of NADPH[nicotinamide adenine dinucleotide phosphate(NADP+), reduced]ATP may never be limiting in thesecells. No matter how much they are stimulatedto divide, cells using aerobic glycolysis alsoexhibit high ratios of ATP/ADP (adenosine 5´-diphosphate) and NADH/NAD+ (2, 9). Further,even minor perturbations in the ATP/ADP ratiocan impair growth. Cells deficient in ATP oftenundergo apoptosis
mechanistic links between cellular metabolism and growth control may ultimately lead to bettertreatments for human cancermost cancer cells insteadrely on aerobic glycolysis, a phenomenon termed “the Warburg effectAerobic glycolysis is aninefficient way to generate adenosine 5´-triphosphate (ATP)the metabolism of cancer cells, is adapted to facilitate the uptake and incorporation of nutrients into thebiomass (e.g., nucleotides, amino acids, and lipids) needed to produce a new cell
mechanistic links between cellular metabolism and growth control may ultimately lead to bettertreatments for human cancermost cancer cells insteadrely on aerobic glycolysis, a phenomenon termed “the Warburg effectAerobic glycolysis is aninefficient way to generate adenosine 5´-triphosphate (ATP)the metabolism of cancer cells, is adapted to facilitate the uptake and incorporation of nutrients into thebiomass (e.g., nucleotides, amino acids, and lipids) needed to produce a new cell
LC-MS/MS to profile the levels of 157different small molecule metabolites (13) in the well characterized4T1 series of cell lines of a murine mammary cancer model(14). This series includes five isogenictumorigenic lines (67NR,168FARN, 4TO7, 66cl4, and 4T1) that originated from onespontaneous tumor in the BALB/cfC3H mouse.We also included a normal murine mammary gland epithelialcell line,NMuMG(15), as the baseline control to observemetabolic changes correlated with tumorigenesis.Several intermediates in glycolysis increased in tumorigeniclines, including hexose phosphate (i.e. glucose-6-phosphateand fructose-6-phosphate) and fructose-1,6-bisphosphateAdditionally, ribose phosphate was significantlyhigher in these cells when compared with NMuMGThe building blockof fatty acids, malonyl-CoA, was also significantly more abundant in tumorigenic lines (Fig. 2A). This result was consistentwith the finding of active fatty acid synthesis in tumor tissues
Nude mice,strain CD1, approximately 5–6 weeks of age and weighing approximately30 g, received s.c. implantation with 100 microliters of human osteosarcoma cell line143b at 10 +7 cells/microl.treatment was delayeduntil the tumors were approximately 300 mm3.ADR ! 2-DG groups received 0.2 ml of 2-DG i.p.at 75 mg/ml (500 mg/kg), which was repeated 3 " per week (Monday,Wednesday, and Friday) for the duration of the experiment. On day 1, the ADRand ADR ! 2-DG groups received 0.3 ml of ADR i.v. at 0.6 mg/ml (6 mg/kg),which was repeated once per week for a total of three treatments (18 mg/kg).2-DG preventingcells from repairing damage caused by ADR or paclitaxel.An alternative explanation for how 2-DG increases the activity ofchemotherapeutic agents is based on the fact that the p-glycoproteineffluxing pumps require ATP for their activity (19). If ATP concentrationsare reduced, as has been reported to occur when cells aretreated in vitro with 2-DG (16), the pumps will cease to function, anddrug accumulation should increase intracellularly, thereby killing thecell.
Hypoxic tumor cells depend on glucose and glycolysis to produce energy. Lactate, the end-product of glycolysis, diffuses along its concentration gra- dient toward blood vessels. By contrast, oxy- genated tumor cells import lactate (a process mediated by MCT1 located at the cell plasma membrane) and oxidize it to produce energy. In the respiration process, lactate is a substrate preferred to glucose. As a consequence, glu- cose freely diffuses through the oxygenated tumor cell sheath to fuel glycolysis of distant, hypoxic tumor cells. This metabolic symbiosis can be disrupted by MCT1 inhibition. lactate oxi- dation does not require the initial energy input that drives ATP production from glucose. Third, respiration of lactate yields 18 ATP per lactate molecule and spares energy normally intended for housekeeping glycolytic enzymes. Lactate oxidation is thus more concise and more effective than glucose in the tumor cell energy metabolism under aerobic conditions.
Unicellularorganisms starved of nutrients rely primarily on oxidative metabolism, as do cells in a multicellular organismthat are not stimulated to proliferate.
