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

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.

[1]  S. Varma,et al.  Formation of advanced glycation end (AGE) products in diabetes: Prevention by pyruvate and a-keto glutarate , 1997, Molecular and Cellular Biochemistry.

[2]  H. Pinedo,et al.  Induction of Vascular Endothelial Growth Factor Expression and Hypoxia-inducible Factor 1α Protein by the Oxidative Stressor Arsenite* , 2001, The Journal of Biological Chemistry.

[3]  L. Yin,et al.  Butyrate Suppression of Colonocyte NF-κB Activation and Cellular Proteasome Activity* , 2001, The Journal of Biological Chemistry.

[4]  M. Gassmann,et al.  HIF‐1 is expressed in normoxic tissue and displays an organ‐specific regulation under systemic hypoxia , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[5]  S. McKnight,et al.  A Conserved Family of Prolyl-4-Hydroxylases That Modify HIF , 2001, Science.

[6]  Michael I. Wilson,et al.  C. elegans EGL-9 and Mammalian Homologs Define a Family of Dioxygenases that Regulate HIF by Prolyl Hydroxylation , 2001, Cell.

[7]  M. Asaka,et al.  Constitutive expression of hypoxia-inducible factor-1alpha renders pancreatic cancer cells resistant to apoptosis induced by hypoxia and nutrient deprivation. , 2001, Cancer research.

[8]  M. Blagosklonny.  Hypoxia-inducible factor: Achilles' heel of antiangiogenic cancer therapy (review). , 2001, International journal of oncology.

[9]  G. Semenza,et al.  Hypoxia-inducible factor 1: oxygen homeostasis and disease pathophysiology. , 2001, Trends in molecular medicine.

[10]  P. Ratcliffe,et al.  Activation of the HIF pathway in cancer. , 2001, Current opinion in genetics & development.

[11]  M. S. Lee,et al.  Angiogenic activity of pyruvic acid in in vivo and in vitro angiogenesis models. , 2001, Cancer research.

[12]  M. Ivan,et al.  HIFα Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O2 Sensing , 2001, Science.

[13]  Michael I. Wilson,et al.  Targeting of HIF-α to the von Hippel-Lindau Ubiquitylation Complex by O2-Regulated Prolyl Hydroxylation , 2001, Science.

[14]  P. Vaupel,et al.  Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. , 2001, Journal of the National Cancer Institute.

[15]  Andrew L. Kung,et al.  Suppression of tumor growth through disruption of hypoxia-inducible transcription , 2000, Nature Medicine.

[16]  J. Pouysségur,et al.  Nonhypoxic pathway mediates the induction of hypoxia-inducible factor 1alpha in vascular smooth muscle cells. , 2000, The Journal of biological chemistry.

[17]  G. Semenza,et al.  Role of hypoxia‐inducible factor‐1 in hypoxia‐induced ischemic tolerance in neonatal rat brain , 2000, Annals of neurology.

[18]  M. Schindl,et al.  Overexpression of hypoxia-inducible factor 1alpha is a marker for an unfavorable prognosis in early-stage invasive cervical cancer. , 2000, Cancer research.

[19]  C. Dang,et al.  Deregulation of Glucose Transporter 1 and Glycolytic Gene Expression by c-Myc* , 2000, The Journal of Biological Chemistry.

[20]  G. Semenza,et al.  Expression of hypoxia‐inducible factor 1α in brain tumors , 2000 .

[21]  G. Semenza.  HIF-1: mediator of physiological and pathophysiological responses to hypoxia. , 2000, Journal of applied physiology.

[22]  G. Semenza,et al.  Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. , 2000, Cancer research.

[23]  G. Semenza,et al.  Hypoxia, Clonal Selection, and the Role of HIF-1 in Tumor Progression , 2000, Critical reviews in biochemistry and molecular biology.

[24]  D A Hilton,et al.  Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. , 1999, Cancer research.

[25]  M. Malatesta,et al.  Growth factors stimulate the activity of key glycolytic enzymes in isolated digestive gland cells from mussels (Mytilus galloprovincialis Lam.) through tyrosine kinase mediated signal transduction. , 1999, General and comparative endocrinology.

[26]  G. Semenza,et al.  Reciprocal positive regulation of hypoxia-inducible factor 1alpha and insulin-like growth factor 2. , 1999, Cancer research.

[27]  Yuichi Makino,et al.  Regulation of the Hypoxia-inducible Transcription Factor 1α by the Ubiquitin-Proteasome Pathway* , 1999, The Journal of Biological Chemistry.

[28]  G. Semenza,et al.  Oncogenic alterations of metabolism. , 1999, Trends in biochemical sciences.

[29]  B. Shilo,et al.  Insulin induces transcription of target genes through the hypoxia‐inducible factor HIF‐1α/ARNT , 1998, The EMBO journal.

[30]  L. Huang,et al.  Regulation of hypoxia-inducible factor 1α is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway , 1998 .

[31]  H. Lyng,et al.  Correlation of high lactate levels in head and neck tumors with incidence of metastasis. , 1997, The American journal of pathology.

[32]  E. Rofstad,et al.  Correlation of high lactate levels in human cervical cancer with incidence of metastasis. , 1995, Cancer research.

[33]  G. Semenza,et al.  Purification and Characterization of Hypoxia-inducible Factor 1 (*) , 1995, The Journal of Biological Chemistry.

[34]  E. Newsholme,et al.  Application of metabolic-control logic to fuel utilization and its significance in tumor cells. , 1991, Advances in enzyme regulation.

[35]  C. V. van Veelen,et al.  The pyruvate kinase isoenzyme shift in human gliomas: a potential marker in the treatment of gliomas. , 1988, British journal of neurosurgery.

[36]  H. Lodish,et al.  Elevated levels of glucose transport and transporter messenger RNA are induced by ras or src oncogenes. , 1987, Science.

[37]  T. Galeotti,et al.  Transport of pyruvate in mitochondria from different tumor cells. , 1983, Cancer research.

[38]  O. Warburg.  [Origin of cancer cells]. , 1956, Oncologia.