2002
DOI: 10.1074/jbc.m202487200
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Hypoxia-inducible Factor 1 Activation by Aerobic Glycolysis Implicates the Warburg Effect in Carcinogenesis

Abstract: Cancer cells display high rates of aerobic glycolysis, a phenomenon known historically as the Warburg effect. Lactate and pyruvate, the end products of glycolysis, are highly produced by cancer cells even in the presence of oxygen. Hypoxia-induced gene expression in cancer cells has been linked to malignant transformation. Here we provide evidence that lactate and pyruvate regulate hypoxia-inducible gene expression independently of hypoxia by stimulating the accumulation of hypoxia-inducible Factor 1␣ (HIF-1␣)… Show more

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Cited by 725 publications
(619 citation statements)
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“…As a key enzyme in the process of glycolysis, LDH converts pyruvate and NADH to lactate and NAD+, determining the maintenance of glycolytic flow and consequently the production of ATP 28. Because LDH can be transcriptionally upregulated by hypoxia inducible factor 1 α (HIF‐1 α ) and hypoxia in the tumor microenviroment is sufficient to stimulate the activation of HIF, there is a positive feedback loop between HIF and LDH under hypoxic conditions 29, 30. Therefore, elevated levels of LDH indicate an aggressive phenotype.…”
Section: Discussionmentioning
confidence: 99%
“…As a key enzyme in the process of glycolysis, LDH converts pyruvate and NADH to lactate and NAD+, determining the maintenance of glycolytic flow and consequently the production of ATP 28. Because LDH can be transcriptionally upregulated by hypoxia inducible factor 1 α (HIF‐1 α ) and hypoxia in the tumor microenviroment is sufficient to stimulate the activation of HIF, there is a positive feedback loop between HIF and LDH under hypoxic conditions 29, 30. Therefore, elevated levels of LDH indicate an aggressive phenotype.…”
Section: Discussionmentioning
confidence: 99%
“…In oxidative TCs and in endothelial cells, it shares with the metabolic lactate pathway the dependency on MCT1 and the need to oxidize lactate into pyruvate, but requires only a low rate of lactate uptake. [6][7][8] While TCs increase their production of vascular endothelial growth factor in response to lactate, 8,9 endothelial cells are triggered to upregulate the expression of vascular endothelial growth factor receptor 2, basic fibroblast growth factor, and interleukin-8, [6][7][8] thus providing several paracrine and autocrine pathways through which lactate induces angiogenesis. Additional activities of lactate in tumors have been reviewed recently.…”
Section: Introductionmentioning
confidence: 99%
“…Glioblastoma multiformes frequently overexpress hypoxiainducible factor-1a, a transcription factor that regulates expression of several glycolytic enzymes (5)(6)(7). High rates of glycolysis may in turn activate hypoxia-inducible factor1a -mediated gene expression (8). Furthermore, glioblastoma multiformes and their normal astrocytic counterparts seem to differ in certain aspects of glucose metabolism; specifically, glioblastoma multiformes exhibit a 3-fold increase in glycolysis (9) and display defects in respiration at various points in the electron transport chain (10).…”
Section: Introductionmentioning
confidence: 99%