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

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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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Author and article information

Journal

Journal ID (iso-abbrev): Cell Rep

Title: Cell reports

Publisher: Elsevier BV

ISSN (Electronic): 2211-1247

Publication date (Electronic): Aug 09 2016

Volume: 16

Issue: 6

Affiliations

[1 ] Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

[2 ] Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

[3 ] McDermott Center for Human Growth and Development, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Molecular Genetics, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

[4 ] Children's Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

[5 ] Department of Cell Biology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

[6 ] Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

[7 ] Department of Veterans Affairs, Palo Alto Health Care System, Palo Alto, CA 94304, USA.

[8 ] Department of Translational Molecular Pathology, MD Anderson Cancer Center, The University of Texas, Houston, TX 7030, USA.

[9 ] Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

[10 ] Department of Molecular Genetics, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

[11 ] Department of Pathology, MD Anderson Cancer Center, The University of Texas, Houston, TX 7030, USA; Departments of Translational Molecular Pathology and Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center, The University of Texas, Houston, TX 7030, USA.

[12 ] McDermott Center for Human Growth and Development, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Children's Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

[13 ] Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: pier.scaglioni@utsouthwestern.edu.