title: An essential requirement for the SCAP/SREBP signaling axis to protect cancer cells from lipotoxicity.
abstract: The sterol regulatory element-binding proteins (SREBP) are key transcriptional regulators of lipid metabolism and cellular growth. It has been proposed that SREBP signaling regulates cellular growth through its ability to drive lipid biosynthesis. Unexpectedly, we find that loss of SREBP activity inhibits cancer cell growth and viability by uncoupling fatty acid synthesis from desaturation. Integrated lipid profiling and metabolic flux analysis revealed that cancer cells with attenuated SREBP activity maintain long-chain saturated fatty acid synthesis, while losing fatty acid desaturation capacity. We traced this defect to the uncoupling of fatty acid synthase activity from stearoyl-CoA desaturase 1 (SCD1)-mediated desaturation. This deficiency in desaturation drives an imbalance between the saturated and monounsaturated fatty acid pools resulting in severe lipotoxicity. Importantly, replenishing the monounsaturated fatty acid pool restored growth to SREBP-inhibited cells. These studies highlight the importance of fatty acid desaturation in cancer growth and provide a novel mechanistic explanation for the role of SREBPs in cancer metabolism.
authors: Department of Pathology and Laboratory Medicine, University of California, Los Angeles 90095, USA.
authors: Kevin J
authors: KJ
authors: Williams
authors: Joseph P
authors: JP
authors: Argus
authors: Yue
authors: Y
authors: Zhu
authors: Moses Q
authors: MQ
authors: Wilks
authors: Beth N
authors: BN
authors: Marbois
authors: Autumn G
authors: AG
authors: York
authors: Yoko
authors: Y
authors: Kidani
authors: Alexandra L
authors: AL
authors: Pourzia
authors: David
authors: D
authors: Akhavan
authors: Dominique N
authors: DN
authors: Lisiero
authors: Evangelia
authors: E
authors: Komisopoulou
authors: Amy H
authors: AH
authors: Henkin
authors: Horacio
authors: H
authors: Soto
authors: Brian T
authors: BT
authors: Chamberlain
authors: Laurent
authors: L
authors: Vergnes
authors: Michael E
authors: ME
authors: Jung
authors: Jorge Z
authors: JZ
authors: Torres
authors: Linda M
authors: LM
authors: Liau
authors: Heather R
authors: HR
authors: Christofk
authors: Robert M
authors: RM
authors: Prins
authors: Paul S
authors: PS
authors: Mischel
authors: Karen
authors: K
authors: Reue
authors: Thomas G
authors: TG
authors: Graeber
authors: Steven J
authors: SJ
authors: Bensinger
mesh_terms: D000818:Animals; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D064429:Fatty Acid Synthases / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D015233:Models, Statistical; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism*; D015398:Signal Transduction; D013230:Stearoyl-CoA Desaturase / Q000378:metabolism; D013261:Sterols / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C102196:SREBP cleavage-activating protein; D013261:Sterols; D013230:Stearoyl-CoA Desaturase; D064429:Fatty Acid Synthases