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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA160458-03
Application #
8657912
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Salnikow, Konstantin
Project Start
2012-07-20
Project End
2017-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
3
Fiscal Year
2014
Total Cost
$309,781
Indirect Cost
$68,251
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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
Wegner, André; Weindl, Daniel; Jäger, Christian et al. (2014) Fragment formula calculator (FFC): determination of chemical formulas for fragment ions in mass spectrometric data. Anal Chem 86:2221-8
Gameiro, Paulo A; Laviolette, Laura A; Kelleher, Joanne K et al. (2013) Cofactor balance by nicotinamide nucleotide transhydrogenase (NNT) coordinates reductive carboxylation and glucose catabolism in the tricarboxylic acid (TCA) cycle. J Biol Chem 288:12967-77
Gameiro, Paulo A; Yang, Juanjuan; Metelo, Ana M et al. (2013) In vivo HIF-mediated reductive carboxylation is regulated by citrate levels and sensitizes VHL-deficient cells to glutamine deprivation. Cell Metab 17:372-85
Nicolay, Brandon N; Gameiro, Paulo A; Tschop, Katrin et al. (2013) Loss of RBF1 changes glutamine catabolism. Genes Dev 27:182-96
Fendt, Sarah-Maria; Bell, Eric L; Keibler, Mark A et al. (2013) Metformin decreases glucose oxidation and increases the dependency of prostate cancer cells on reductive glutamine metabolism. Cancer Res 73:4429-38
Fendt, Sarah-Maria; Bell, Eric L; Keibler, Mark A et al. (2013) Reductive glutamine metabolism is a function of the *-ketoglutarate to citrate ratio in cells. Nat Commun 4:2236