We recently identified a novel link between hypoxia, which is a hallmark of human malignancies, and cancer cell metabolism. We showed that hypoxia dramatically induces a previously under-appreciated metabolic pathway in cancer cells, namely the generation of cytosolic Acetyl-Coa (AcCoA) by reductive carboxylation of cytosolic ?-ketoglutarate (?KG) to isocitrate. Our preliminary data indicate that Isocitrate Dehydrogenase 1, an enzyme mutated in gliomas and acute leukemias, is necessary for this phenomenon and that the transcription factors Hypoxia Inducible Factors (HIFs) and the hypoxia-regulated cytosolic enzyme Aco1 are likely implicated in mediating this hypoxia effect. Our work highlights that hypoxia-induced metabolic changes of cancer cells present an opportunity for development of therapies targeting a broad range of human malignancies. In this application we propose to dissect the molecular mechanism(s) mediating the hypoxia-induced reductive carboxylation by and to validate critical enzymes of reductive carboxylation as therapeutic targets for tumor suppression in vivo.
Cancer cells have a metabolism which differs from the metabolism of normal cells. In addition, almost all cancers learn how to grow in hypoxic environments. We discovered a new mechanism that links hypoxia and cancer cell metabolism and we propose experiments that will highlight the molecular mechanisms of this link and will identify critical proteins that can target this mechanism for anti-cancer therapy. This is an underappreciated area of work that opens new opportunities for cancer therapy.
|Noonan, Haley R; Metelo, Ana M; Kamei, Caramai N et al. (2016) Loss of vhl in the zebrafish pronephros recapitulates early stages of human clear cell renal cell carcinoma. Dis Model Mech 9:873-84|
|Keibler, Mark A; Wasylenko, Thomas M; Kelleher, Joanne K et al. (2016) Metabolic requirements for cancer cell proliferation. Cancer Metab 4:16|
|Lunt, Sophia Y; Muralidhar, Vinayak; Hosios, Aaron M et al. (2015) Pyruvate kinase isoform expression alters nucleotide synthesis to impact cell proliferation. Mol Cell 57:95-107|
|Metelo, Ana Martins; Noonan, Haley; Iliopoulos, Othon (2015) HIF2a inhibitors for the treatment of VHL disease. Oncotarget 6:23036-7|
|Wasylenko, Thomas M; Stephanopoulos, Gregory (2015) Metabolomic and (13)C-metabolic flux analysis of a xylose-consuming Saccharomyces cerevisiae strain expressing xylose isomerase. Biotechnol Bioeng 112:470-83|
|Buescher, Joerg M; Antoniewicz, Maciek R; Boros, Laszlo G et al. (2015) A roadmap for interpreting (13)C metabolite labeling patterns from cells. Curr Opin Biotechnol 34:189-201|
|Black, Joshua C; Atabakhsh, Elnaz; Kim, Jaegil et al. (2015) Hypoxia drives transient site-specific copy gain and drug-resistant gene expression. Genes Dev 29:1018-31|
|Metelo, Ana Martins; Noonan, Haley R; Li, Xiang et al. (2015) Pharmacological HIF2Î± inhibition improves VHL disease-associated phenotypes in zebrafish model. J Clin Invest 125:1987-97|
|Vasdekis, Andreas E; Stephanopoulos, Gregory (2015) Review of methods to probe single cell metabolism and bioenergetics. Metab Eng 27:115-35|
|Zhang, Jie; Ahn, Woo Suk; Gameiro, Paulo A et al. (2014) 13C isotope-assisted methods for quantifying glutamine metabolism in cancer cells. Methods Enzymol 542:369-89|
Showing the most recent 10 out of 20 publications