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 journalArticle

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 languageEnglish (US)
Pages (from-to)1614-1628
Number of pages15
JournalCell Reports
Volume16
Issue number6
DOIs
StatePublished - 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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  • Cite this

    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