Cell Reports
(Aug 2016)
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
Affiliations
Mahesh S. Padanad
Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Georgia Konstantinidou
Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Niranjan Venkateswaran
Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Margherita Melegari
Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Smita Rindhe
Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Matthew Mitsche
McDermott Center for Human Growth and Development, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Chendong Yang
Children’s Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Kimberly Batten
Department of Cell Biology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Kenneth E. Huffman
Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Jingwen Liu
Department of Veterans Affairs, Palo Alto Health Care System, Palo Alto, CA 94304, USA
Ximing Tang
Department of Translational Molecular Pathology, MD Anderson Cancer Center, The University of Texas, Houston, TX 7030, USA
Jaime Rodriguez-Canales
Department of Translational Molecular Pathology, MD Anderson Cancer Center, The University of Texas, Houston, TX 7030, USA
Neda Kalhor
Department of Translational Molecular Pathology, MD Anderson Cancer Center, The University of Texas, Houston, TX 7030, USA
Jerry W. Shay
Department of Cell Biology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
John D. Minna
Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Jeffrey McDonald
Department of Molecular Genetics, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Ignacio I. Wistuba
Department of Pathology, MD Anderson Cancer Center, The University of Texas, Houston, TX 7030, USA
Ralph J. DeBerardinis
McDermott Center for Human Growth and Development, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Pier Paolo Scaglioni
Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
DOI
https://doi.org/10.1016/j.celrep.2016.07.009
Journal volume & issue
Vol. 16,
no. 6
Abstract
Read online
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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