| Literature DB >> 27477280 |
Mahesh S Padanad1, Georgia Konstantinidou1, Niranjan Venkateswaran1, Margherita Melegari2, Smita Rindhe1, Matthew Mitsche3, Chendong Yang4, Kimberly Batten5, Kenneth E Huffman6, Jingwen Liu7, Ximing Tang8, Jaime Rodriguez-Canales8, Neda Kalhor8, Jerry W Shay5, John D Minna9, Jeffrey McDonald10, Ignacio I Wistuba11, Ralph J DeBerardinis12, Pier Paolo Scaglioni13.
Abstract
KRAS is one of the most commonly mutated oncogenes in human cancer. Mutant KRAS aberrantly regulates metabolic networks. However, the contribution of cellular metabolism to mutant KRAS tumorigenesis is not completely understood. We report that mutant KRAS regulates intracellular fatty acid metabolism through Acyl-coenzyme A (CoA) synthetase long-chain family member 3 (ACSL3), which converts fatty acids into fatty Acyl-CoA esters, the substrates for lipid synthesis and β-oxidation. ACSL3 suppression is associated with depletion of cellular ATP and causes the death of lung cancer cells. Furthermore, mutant KRAS promotes the cellular uptake, retention, accumulation, and β-oxidation of fatty acids in lung cancer cells in an ACSL3-dependent manner. Finally, ACSL3 is essential for mutant KRAS lung cancer tumorigenesis in vivo and is highly expressed in human lung cancer. Our data demonstrate that mutant KRAS reprograms lipid homeostasis, establishing a metabolic requirement that could be exploited for therapeutic gain.Entities:
Keywords: ACSL3; cancer metabolism; fatty acid oxidation; lipid metabolism; lung cancer; mouse cancer models; mutant KRAS
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Year: 2016 PMID： 27477280 PMCID： PMC4981512 DOI： 10.1016/j.celrep.2016.07.009
Source DB: PubMed Journal: Cell Rep Impact factor: 9.423