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

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

doi:10.1016/j.celrep.2016.07.009

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

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

Research output: Contribution to journal › Article

49 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1614-1628
Number of pages	15
Journal	Cell Reports
Volume	16
Issue number	6
DOIs	https://doi.org/10.1016/j.celrep.2016.07.009
State	Published - Aug 9 2016

Keywords

ACSL3
cancer metabolism
fatty acid oxidation
lipid metabolism
lung cancer
mouse cancer models
mutant KRAS

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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Padanad, M. S., Konstantinidou, G., Venkateswaran, N., Melegari, M., Rindhe, S., Mitsche, M., Yang, C., Batten, K., Huffman, K. E., Liu, J., Tang, X., Rodriguez-Canales, J., Kalhor, N., Shay, J. W., Minna, J. D., McDonald, J., Wistuba, I. I., DeBerardinis, R. J., & Scaglioni, P. P. (2016). Fatty Acid Oxidation Mediated by Acyl-CoA Synthetase Long Chain 3 Is Required for Mutant KRAS Lung Tumorigenesis. Cell Reports, 16(6), 1614-1628. https://doi.org/10.1016/j.celrep.2016.07.009

Fatty Acid Oxidation Mediated by Acyl-CoA Synthetase Long Chain 3 Is Required for Mutant KRAS Lung Tumorigenesis. / Padanad, Mahesh S.; Konstantinidou, Georgia; Venkateswaran, Niranjan; Melegari, Margherita; Rindhe, Smita; Mitsche, Matthew; Yang, Chendong; Batten, Kimberly; Huffman, Kenneth E.; Liu, Jingwen; Tang, Ximing; Rodriguez-Canales, Jaime; Kalhor, Neda; Shay, Jerry W.; Minna, John D.; McDonald, Jeffrey; Wistuba, Ignacio I.; DeBerardinis, Ralph J.; Scaglioni, Pier Paolo.

In: Cell Reports, Vol. 16, No. 6, 09.08.2016, p. 1614-1628.

Research output: Contribution to journal › Article

Padanad, MS, Konstantinidou, G, Venkateswaran, N, Melegari, M, Rindhe, S, Mitsche, M, Yang, C, Batten, K, Huffman, KE, Liu, J, Tang, X, Rodriguez-Canales, J, Kalhor, N, Shay, JW , Minna, JD , McDonald, J, Wistuba, II, DeBerardinis, RJ & Scaglioni, PP 2016, 'Fatty Acid Oxidation Mediated by Acyl-CoA Synthetase Long Chain 3 Is Required for Mutant KRAS Lung Tumorigenesis', Cell Reports, vol. 16, no. 6, pp. 1614-1628. https://doi.org/10.1016/j.celrep.2016.07.009

Padanad, Mahesh S. ; Konstantinidou, Georgia ; Venkateswaran, Niranjan ; Melegari, Margherita ; Rindhe, Smita ; Mitsche, Matthew ; Yang, Chendong ; Batten, Kimberly ; Huffman, Kenneth E. ; Liu, Jingwen ; Tang, Ximing ; Rodriguez-Canales, Jaime ; Kalhor, Neda ; Shay, Jerry W. ; Minna, John D. ; McDonald, Jeffrey ; Wistuba, Ignacio I. ; DeBerardinis, Ralph J. ; Scaglioni, Pier Paolo. / Fatty Acid Oxidation Mediated by Acyl-CoA Synthetase Long Chain 3 Is Required for Mutant KRAS Lung Tumorigenesis. In: Cell Reports. 2016 ; Vol. 16, No. 6. pp. 1614-1628.

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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.",

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AU - McDonald, Jeffrey

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