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

Cell Reports

Chendong Yang¹  Kimberly Batten²  Jerry W. Shay²  Niranjan Venkateswaran³  Pier Paolo Scaglioni³  Smita Rindhe³  Mahesh S. Padanad³  John D. Minna³  Georgia Konstantinidou³  Jeffrey McDonald⁴  Ignacio I. Wistuba⁵  Neda Kalhor⁶  Ximing Tang⁶  Jaime Rodriguez-Canales⁶  Jingwen Liu⁷  Kenneth E. Huffman⁸  Matthew Mitsche⁹  Ralph J. DeBerardinis⁹  Margherita Melegari^1,10 

[1] Children’s Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA;Department of Cell Biology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA;Department of Internal Medicine, 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;Department of Pathology, MD Anderson Cancer Center, The University of Texas, Houston, TX 7030, USA;Department of Translational Molecular Pathology, MD Anderson Cancer Center, The University of Texas, Houston, TX 7030, USA;Department of Veterans Affairs, Palo Alto Health Care System, Palo Alto, CA 94304, USA;Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA;McDermott Center for Human Growth and Development, 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;

关键词: ACSL3;    mutant KRAS;    lung cancer;    cancer metabolism;    fatty acid oxidation;    lipid metabolism;    mouse cancer models;   

DOI  :  10.1016/j.celrep.2016.07.009

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown