Fatty Acid Oxidation Mediated by Acyl-CoA Synthetase Long Chain 3 Is Required for Mutant KRAS Lung Tumorigenesis | Zendy

Mahesh S. Padanad | Zendy; Georgia Konstantinidou | Zendy; Niranjan Venkateswaran | Zendy; Margherita Melegari | Zendy; Smita Rindhe | Zendy; Matthew A. Mitsche | Zendy; Chendong Yang | Zendy; Kimberly Batten | Zendy; Kenneth E. Huffman | Zendy; Jingwen Liu | Zendy; Ximing Tang | Zendy; Jaime RodriguezCanales | Zendy; Neda Kalhor | Zendy; Jerry W. Shay | Zendy; John D. Minna | Zendy; Jeffrey G. McDonald | Zendy; Ignacio I. Wistuba | Zendy; Ralph J. DeBerardinis | Zendy; Pier Paolo Scaglioni | Zendy

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Fatty Acid Oxidation Mediated by Acyl-CoA Synthetase Long Chain 3 Is Required for Mutant KRAS Lung Tumorigenesis

Author(s) -

Mahesh S. Padanad,

Georgia Konstantinidou,

Niranjan Venkateswaran,

Margherita Melegari,

Smita Rindhe,

Matthew A. Mitsche,

Chendong Yang,

Kimberly Batten,

Kenneth E. Huffman,

Jingwen Liu,

Ximing Tang,

Jaime RodriguezCanales,

Neda Kalhor,

Jerry W. Shay,

John D. Minna,

Jeffrey G. McDonald,

Ignacio I. Wistuba,

Ralph J. DeBerardinis,

Pier Paolo Scaglioni

Publication year - 2016

Publication title -

cell reports

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 6.264

H-Index - 154

eISSN - 2639-1856

pISSN - 2211-1247

DOI - 10.1016/j.celrep.2016.07.009

Subject(s) - kras , carcinogenesis , biology , mutant , lipid metabolism , fatty acid metabolism , cancer cell , beta oxidation , cancer research , biochemistry , fatty acid , microbiology and biotechnology , cancer , mutation , gene , genetics

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.

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