| Literature DB >> 26678339 |
Kensuke Tateishi1, Hiroaki Wakimoto1, A John Iafrate2, Shota Tanaka3, Franziska Loebel1, Nina Lelic1, Dmitri Wiederschain4, Olivier Bedel4, Gejing Deng4, Bailin Zhang4, Timothy He4, Xu Shi5, Robert E Gerszten5, Yiyun Zhang5, Jing-Ruey J Yeh5, William T Curry1, Dan Zhao3, Sudhandra Sundaram3, Fares Nigim1, Mara V A Koerner1, Quan Ho2, David E Fisher6, Elisabeth M Roider6, Lajos V Kemeny6, Yardena Samuels7, Keith T Flaherty8, Tracy T Batchelor3, Andrew S Chi9, Daniel P Cahill10.
Abstract
Heterozygous mutation of IDH1 in cancers modifies IDH1 enzymatic activity, reprogramming metabolite flux and markedly elevating 2-hydroxyglutarate (2-HG). Here, we found that 2-HG depletion did not inhibit growth of several IDH1 mutant solid cancer types. To identify other metabolic therapeutic targets, we systematically profiled metabolites in endogenous IDH1 mutant cancer cells after mutant IDH1 inhibition and discovered a profound vulnerability to depletion of the coenzyme NAD+. Mutant IDH1 lowered NAD+ levels by downregulating the NAD+ salvage pathway enzyme nicotinate phosphoribosyltransferase (Naprt1), sensitizing to NAD+ depletion via concomitant nicotinamide phosphoribosyltransferase (NAMPT) inhibition. NAD+ depletion activated the intracellular energy sensor AMPK, triggered autophagy, and resulted in cytotoxicity. Thus, we identify NAD+ depletion as a metabolic susceptibility of IDH1 mutant cancers.Entities:
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Year: 2015 PMID： 26678339 PMCID： PMC4684594 DOI： 10.1016/j.ccell.2015.11.006
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743