JHIBRG:Abstract July 5 2007

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Effects of c-Myc and HIF-1 on Tumor Metabolism

Normal tissues convert glucose to pyruvate which is taken up by mitochondria and further metabolized through TCA cycle. From a pyruvate, TCA cycle generates NADH and FADH2 which establish a proton gradient through donating high-energy electrons and produce ATP. The Pasteur effect, which describes the increased conversion of glucose to lactate in hypoxic cells to compensate impaired ATP generation, has been considered a critical cellular metabolic adaptation to hypoxia. In contrast to normal tissues, many types of cancer cells display an aberrantly enhanced glycolysis even in the presence of oxygen, termed the Warburg effect. MYC is one of the oncogenic factors to contribute to an activation of aerobic glycolysis. We performed a comprehensive analysis of the network of MYC and all glycolytic enzyme genes using phylogenetic footprinting analysis and a chromatin immunoprecipitation assay. Not only validates phylogenetic footprinting analysis, but our approach also delineates the molecular basis of MYC-induced altered glucose metabolism. HIF-1 is a transcription factor, which functions as a master regulator of oxygen homeostasis. Interestingly, the consensus binding site for MYC (5'-CACGTG-3') is similar to the HIF-1 consensus binding site 5’-RCGTG-3’. Thus, we asked if HIF-1 may cooperate with oncogenic event such as MYC activation to allow cells to adapt in response to the hypoxic microenvironment. We demonstrate that expressions of a key glycolytic enzyme, hexokinase 2, and VEGF are further enhanced when cells express both MYC and HIF-1 suggesting that oncogenic activation cooperates with cellular metabolic adaptation to hypoxia. We further sought to determine by microarray analysis the overlap of genes responsive to both MYC and hypoxia. Among the gene highly induced by hypoxia is PDK1 which phosphorylates and inactivates pyruvate dehydrogenase (PDH), the enzyme that converts pyruvate to acetyl CoA, thereby inhibiting glucose metabolism via the TCA cycle. Under hypoxic conditions, HIF1 alpha-null MEFs undergo apoptosis that is associated with a dramatic increase in the level of ROS. Forced expression of PDK1 prevents hypoxia induced ROS generation and apoptosis. These suggest a failure of the electron transport chain under hypoxic conditions, which necessitates the shunting of glucose metabolite away from the mitochondria by HIF-1-mediated PDK1 expression in order to prevent catastrophic ROS production.


References

Jung-whan Kim, Ping Gao, and Chi V. Dnag. Effects of hypoxia on tumor metabolism. Cancer and Metastasis Reviews. (2007) In press

Jung-whan Kim, and Chi V. Dang. Cancer’s molecular sweet tooth and the Warburg effect. Cancer Research 66:8927-8930 (2006)

Jung-whan Kim, Irina Tchernyshyov, Gregg L. Semenza, and Chi V. Dang. HIF-1-mediated expression of PDK: a metabolic switch required for cellular adaptation to hypoxia. Cell Metabolism, 3:177-185 (2006)

Jung-whan Kim, Lawrence B. Gardner and Chi V. Dang. Oncogenic Alterations of Metabolism and the Warburg Effect. Drug Discovery Today: Disease Mechanisms, 2:233-235 (2005)

Jung-whan Kim and Chi V. Dang. Multifaceted Roles of Glycolytic Enzymes. Trends in Biochemical Sciences, 30:142-150 (2005)

Jung-whan Kim, Karen I. Zeller, Yunyue Wang, Anil G. Jegga, Bruce J. Aronow, Kathryn A. O’Donnell, and Chi V. Dang. Evaluation of Myc E-Box Phylogenetic Footprints in Glycolytic Genes by Chromatin Immunoprecipitation Assays. Molecular and Cellular Biology, 24:5923-5936 (2004)

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