TY - JOUR
T1 - Fatty Acid Oxidation Mediated by Acyl-CoA Synthetase Long Chain 3 Is Required for Mutant KRAS Lung Tumorigenesis
AU - Padanad, Mahesh S.
AU - Konstantinidou, Georgia
AU - Venkateswaran, Niranjan
AU - Melegari, Margherita
AU - Rindhe, Smita
AU - Mitsche, Matthew
AU - Yang, Chendong
AU - Batten, Kimberly
AU - Huffman, Kenneth E.
AU - Liu, Jingwen
AU - Tang, Ximing
AU - Rodriguez-Canales, Jaime
AU - Kalhor, Neda
AU - Shay, Jerry W.
AU - Minna, John D.
AU - McDonald, Jeffrey
AU - Wistuba, Ignacio I.
AU - DeBerardinis, Ralph J.
AU - Scaglioni, Pier Paolo
N1 - Publisher Copyright:
© 2016 The Authors
PY - 2016/8/9
Y1 - 2016/8/9
N2 - 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.
AB - 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.
KW - ACSL3
KW - cancer metabolism
KW - fatty acid oxidation
KW - lipid metabolism
KW - lung cancer
KW - mouse cancer models
KW - mutant KRAS
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U2 - 10.1016/j.celrep.2016.07.009
DO - 10.1016/j.celrep.2016.07.009
M3 - Article
C2 - 27477280
AN - SCOPUS:84979738962
SN - 2211-1247
VL - 16
SP - 1614
EP - 1628
JO - Cell Reports
JF - Cell Reports
IS - 6
ER -