title: Fatty Acid Oxidation Mediated by Acyl-CoA Synthetase Long Chain 3 Is Required for Mutant KRAS Lung Tumorigenesis.
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.
authors.affiliation: 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.
authors.forename: Mahesh S
authors.initials: MS
authors.lastname: Padanad
authors.affiliation: 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.
authors.forename: Georgia
authors.initials: G
authors.lastname: Konstantinidou
authors.affiliation: 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.
authors.forename: Niranjan
authors.initials: N
authors.lastname: Venkateswaran
authors.affiliation: Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Margherita
authors.initials: M
authors.lastname: Melegari
authors.affiliation: 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.
authors.forename: Smita
authors.initials: S
authors.lastname: Rindhe
authors.affiliation: 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.
authors.forename: Matthew
authors.initials: M
authors.lastname: Mitsche
authors.affiliation: Children's Medical Center Research Institute, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Chendong
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Cell Biology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Batten
authors.affiliation: Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Huffman
authors.affiliation: Department of Veterans Affairs, Palo Alto Health Care System, Palo Alto, CA 94304, USA.
authors.forename: Jingwen
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Translational Molecular Pathology, MD Anderson Cancer Center, The University of Texas, Houston, TX 7030, USA.
authors.forename: Ximing
authors.initials: X
authors.lastname: Tang
authors.affiliation: Department of Translational Molecular Pathology, MD Anderson Cancer Center, The University of Texas, Houston, TX 7030, USA.
authors.forename: Jaime
authors.initials: J
authors.lastname: Rodriguez-Canales
authors.affiliation: Department of Translational Molecular Pathology, MD Anderson Cancer Center, The University of Texas, Houston, TX 7030, USA.
authors.forename: Neda
authors.initials: N
authors.lastname: Kalhor
authors.affiliation: Department of Cell Biology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Jerry W
authors.initials: JW
authors.lastname: Shay
authors.affiliation: 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.
authors.forename: John D
authors.initials: JD
authors.lastname: Minna
authors.affiliation: Department of Molecular Genetics, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: McDonald
authors.affiliation: 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.
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
authors.affiliation: 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.
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: DeBerardinis
authors.affiliation: 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.
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Scaglioni
mesh_terms: D000214:Acyl Coenzyme A / Q000378:metabolism*; D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D003066:Coenzyme A Ligases / Q000235:genetics* / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D006801:Humans; D008025:Ligases / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics; D050155:Lipogenesis / Q000502:physiology; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D000098859:Long-Chain-Fatty-Acid-CoA Ligase
chemical_list: D000214:Acyl Coenzyme A; D005227:Fatty Acids; C117307:KRAS protein, human; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D008025:Ligases; D003066:Coenzyme A Ligases; D000098859:Long-Chain-Fatty-Acid-CoA Ligase
keywords: ACSL3; cancer metabolism; fatty acid oxidation; lipid metabolism; lung cancer; mouse cancer models; mutant KRAS