title: SCD1 inhibition causes cancer cell death by depleting mono-unsaturated fatty acids.
abstract: Increased metabolism is a requirement for tumor cell proliferation. To understand the dependence of tumor cells on fatty acid metabolism, we evaluated various nodes of the fatty acid synthesis pathway. Using RNAi we have demonstrated that depletion of fatty-acid synthesis pathway enzymes SCD1, FASN, or ACC1 in HCT116 colon cancer cells results in cytotoxicity that is reversible by addition of exogenous fatty acids. This conditional phenotype is most pronounced when SCD1 is depleted. We used this fatty-acid rescue strategy to characterize several small-molecule inhibitors of fatty acid synthesis, including identification of TOFA as a potent SCD1 inhibitor, representing a previously undescribed activity for this compound. Reference FASN and ACC inhibitors show cytotoxicity that is less pronounced than that of TOFA, and fatty-acid rescue profiles consistent with their proposed enzyme targets. Two reference SCD1 inhibitors show low-nanomolar cytotoxicity that is offset by at least two orders of magnitude by exogenous oleate. One of these inhibitors slows growth of HCT116 xenograft tumors. Our data outline an effective strategy for interrogation of on-mechanism potency and pathway-node-specificity of fatty acid synthesis inhibitors, establish an unambiguous link between fatty acid synthesis and cancer cell survival, and point toward SCD1 as a key target in this pathway.
authors.affiliation: Genzyme Corporation, Waltham, Massachusetts, United States of America. paul.mason@genzyme.com
authors.forename: Paul
authors.initials: P
authors.lastname: Mason
authors.forename: Beirong
authors.initials: B
authors.lastname: Liang
authors.forename: Lingyun
authors.initials: L
authors.lastname: Li
authors.forename: Trisha
authors.initials: T
authors.lastname: Fremgen
authors.forename: Erin
authors.initials: E
authors.lastname: Murphy
authors.forename: Angela
authors.initials: A
authors.lastname: Quinn
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Madden
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Biemann
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.forename: Aharon
authors.initials: A
authors.lastname: Cohen
authors.forename: Svetlana
authors.initials: S
authors.lastname: Komarnitsky
authors.forename: Kate
authors.initials: K
authors.lastname: Jancsics
authors.forename: Brad
authors.initials: B
authors.lastname: Hirth
authors.forename: Christopher G F
authors.initials: CG
authors.lastname: Cooper
authors.forename: Edward
authors.initials: E
authors.lastname: Lee
authors.forename: Sean
authors.initials: S
authors.lastname: Wilson
authors.forename: Roy
authors.initials: R
authors.lastname: Krumbholz
authors.forename: Steven
authors.initials: S
authors.lastname: Schmid
authors.forename: Yibin
authors.initials: Y
authors.lastname: Xiang
authors.forename: Michael
authors.initials: M
authors.lastname: Booker
authors.forename: James
authors.initials: J
authors.lastname: Lillie
authors.forename: Kara
authors.initials: K
authors.lastname: Carter
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D045744:Cell Line, Tumor; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000473:pathology*; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D005229:Fatty Acids, Monounsaturated; C523776:SCD1 protein, human; D013230:Stearoyl-CoA Desaturase