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␣). In human gliomas and other cancer cell lines, the accumulation of HIF-1␣ protein under aerobic conditions requires the metabolism of glucose to pyruvate that prevents the aerobic degradation of HIF-1␣ 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.Cancer cell energy metabolism deviates significantly from that of normal tissues. Cancer cells maintain high aerobic glycolytic rates and produce high levels of lactate and pyruvate (1). This phenomenon was first described in cancer more than seven decades ago and is known historically as the Warburg effect (2, 3). Preferential reliance on glycolysis is correlated with disease progression in several types of cancers (4, 5), and the activities of hexokinase, phosphofructokinase, and pyruvate kinase are consistently and significantly increased in cancer cells (6 -8). Although oncogenes such as ras, src, and myc have been found to enhance aerobic glycolysis by increasing the expression of glucose transporters and glycolytic enzymes (8 -10), the relevance of the Warburg effect to cancer cell biology has remained obscure. Hypoxia is another common feature of many solid cancers and has been linked to malignant transformation, metastasis, and treatment resistance (11). The adaptation of cancer cells to hypoxia is mediated via hypoxia-inducible Factor 1 (HIF-1), 1 a key transcription factor that upregulates a series of genes involved in glycolytic energy metabolism, angiogenesis, cell survival, and erythropoiesis. Included among these genes are vascular endothelial growth factor (VEGF), erythropoietin (EPO), glucose transporters (GLUT), and several glycolytic enzymes (12, 13). HIF-1 is a heterodimer composed of two subunits, HIF-1␣ and HIF-1␤ (14), both of which are constitutively expressed in mammalian cells. The regulation of the HIF-1 complex is mainly dependent on the degradation of the HIF-1␣ subunit. Under nonhypoxic conditions, HIF-1␣ undergoes ubiquination and proteasomal degradation (15,16). This process involves the binding of the von Hippel-Lindau tumor suppressor protein to an oxygen-dependent degradation domain on the HIF-1␣ protein. A family of prolyl hydroxylase enzymes regulates the binding of...

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