Hypoxia-inducible Factor 1 Activation by Aerobic Glycolysis Implicates the Warburg Effect in Carcinogenesis*

By Huasheng Lu, R. Forbes, A. Verma. Journal of Biological Chemistry, 2002

863 citations recorded by the source corpus.

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 1α (HIF-1α). In human gliomas and other cancer cell lines, the accumulation of HIF-1α protein under aerobic conditions requires the metabolism of glucose to pyruvate that prevents the aerobic degradation of HIF-1α protein, activates HIF-1 DNA binding activity, and enhances the expression of several HIF-1-activated genes including erythropoietin, vascular endothelial growth factor, glucose transporter 3, and aldolase A. Our findings support a novel role for pyruvate in metabolic signaling and suggest a mechanism by which high rates of aerobic glycolysis can promote the malignant transformation and survival of cancer cells.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/beb2f0f232466cdc776c7425267e8d0511c8ac52

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Citations in the corpus

Acid-mediated tumor invasion: a multidisciplinary study. (2006, background): “However, constitutive up-regulation of glycolysis is also observed even in the presence of adequate oxygen supplies (aerobic glycolysis): a phenomenon first noted by Warburg >80 years ago (13, 14).”
Causes and Consequences of Increased Glucose Metabolism of Cancers (2008, background): “Notably, reductions in PDH activity through the aforementioned mechanisms may result in increased pyruvate and lactate levels, and these will stabilize HIF-1 in an oxygen-independent manner (95).”
The Histone Deacetylase SIRT6 Regulates Glucose Homeostasis via Hif1α (2010, neutral): “Previous studies have shown that conditions of nutrient stress and increase in lactate production can function as a positive feedback to induce both protein synthesis and stability of Hif1a (Lu et al., 2002; Hirota and Semenza, 2005).”
Redox Regulation of Cell Survival (2008, positive): “In tumor cells, HIF plays a major role in the metabolic switch that shunts glucose metabolites from mitochondria respiration to cytosolic glycolysis (Warburg effect) (194).”
Hypoxia-Inducible Factor-1 (HIF-1) (2006, neutral): “regulate hypoxia-inducible gene expression, hence establishing a potential positive feedback loop (Lu et al., 2002).”
Cancer cell metabolism: Warburg and beyond. (2008, background): “Indeed, acidosis often precedes angiogenesis, and lactate may stimulate HIF expression independently of hypoxia (Fukumura et al., 2001; Lu et al., 2002; Shi et al., 2001).”
Lactate: a metabolic key player in cancer. (2011, background): “Note that HIF-1a is stabilized even under normoxic conditions by the products of glycolysis, lactate and pyruvate, which leads to an accumulation of this master transcription factor (5).”
ADAPTIVE AND MALADAPTIVE CARDIORESPIRATORY RESPONSES TO CONTINUOUS AND INTERMITTENT HYPOXIA MEDIATED BY HYPOXIA-INDUCIBLE FACTORS 1 AND 2 (2012, background): “Small molecule messengers, such as nitric oxide (NO) and prostaglandin E2 (93, 158), as well as metabolites, such as lactate, fumarate, and succinate (131, 202, 296), also increase the levels of HIF-1 protein under nonhypoxic conditions.”
HIF-1 as a target for drug development (2003, background): “This overexpression of HIF-1α is due to both hypoxia-dependent as well as hypoxia-independent pathways, such as oncogene activation and glucose deprivatio”
Transcriptional Regulation by Hypoxia Inducible Factors (2013, background): “For example, accumulation of lactate and pyruvate has been found to result in oxygen-independent HIF stabilization (Lu et al., 2002).”
Why do cancers have high aerobic glycolysis? (2004, background): “Although HIF1α strongly links aerobic glycolysis to carcinogenesi”
Mitochondria in cancer cells: what is so special about them? (2008, positive): “A similar stabilizing effect was described for lactate and pyruvate [ 12 ].”
The Science and Translation of Lactate Shuttle Theory. (2018, background): “Further, the master transcription factor involved in tumor cell glycolysis, HIF-1, has been shown to be activated by lactate in different cancer lines (De Saedeleer et al., 2012; Lu et al., 2002; Semenza, 2010).”