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

Cell Rep. 2016 Aug 9;16(6):1614-1628. doi: 10.1016/j.celrep.2016.07.009. Epub 2016 Jul 28.

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.

Keywords: ACSL3; cancer metabolism; fatty acid oxidation; lipid metabolism; lung cancer; mouse cancer models; mutant KRAS.

MeSH terms

  • Acyl Coenzyme A / metabolism*
  • Animals
  • Carcinogenesis / metabolism
  • Cell Transformation, Neoplastic / metabolism
  • Coenzyme A Ligases / genetics*
  • Coenzyme A Ligases / metabolism
  • Fatty Acids / metabolism
  • Humans
  • Ligases / metabolism
  • Lipid Metabolism / genetics
  • Lipogenesis / physiology
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / metabolism
  • Mice, Knockout
  • Oxidation-Reduction
  • Proto-Oncogene Proteins p21(ras) / genetics*

Substances

  • Acyl Coenzyme A
  • Fatty Acids
  • KRAS protein, human
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)
  • Ligases
  • Coenzyme A Ligases
  • long-chain-fatty-acid-CoA ligase