title: Cancer cell dependence on unsaturated fatty acids implicates stearoyl-CoA desaturase as a target for cancer therapy.
abstract: Emerging literature suggests that metabolic pathways play an important role in the maintenance and progression of human cancers. In particular, recent studies have implicated lipid biosynthesis and desaturation as a requirement for tumor cell survival. In the studies reported here, we aimed to understand whether tumor cells require the activity of either human isoform of stearoyl-CoA-desaturase (SCD1 or SCD5) for survival. Inhibition of SCD1 by siRNA or a small molecule antagonist results in strong induction of apoptosis and growth inhibition, when tumor cells are cultured in reduced (2%) serum conditions, but has little impact on cells cultured in 10% serum. Depletion of SCD5 had minimal effects on cell growth or apoptosis. Consistent with the observed dependence on SCD1, but not SCD5, levels of SCD1 protein increased in response to decreasing serum levels. Both induction of SCD1 protein and sensitivity to growth inhibition by SCD1 inhibition could be reversed by supplementing growth media with unsaturated fatty acids, the product of the enzymatic reaction catalyzed by SCD1. Transcription profiling of cells treated with an SCD inhibitor revealed strong induction of markers of endoplasmic reticulum stress. Underscoring its importance in cancer, SCD1 protein was found to be highly expressed in a large percentage of human cancer specimens. SCD inhibition resulted in tumor growth delay in a human gastric cancer xenograft model. Altogether, these results suggest that desaturated fatty acids are required for tumor cell survival and that SCD may represent a viable target for the development of novel agents for cancer therapy.
authors.affiliation: Department of Oncology Drug Discovery, Bristol-Myers Squibb R&D, Princeton, NJ 08543, USA.
authors.forename: Urvashi V
authors.initials: UV
authors.lastname: Roongta
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Pabalan
authors.forename: Xinyu
authors.initials: X
authors.lastname: Wang
authors.forename: Rolf-Peter
authors.initials: RP
authors.lastname: Ryseck
authors.forename: Joseph
authors.initials: J
authors.lastname: Fargnoli
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Henley
authors.forename: Wen-Pin
authors.initials: WP
authors.lastname: Yang
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
authors.forename: Malavi T
authors.initials: MT
authors.lastname: Madireddi
authors.forename: R Michael
authors.initials: RM
authors.lastname: Lawrence
authors.forename: Tai W
authors.initials: TW
authors.lastname: Wong
authors.forename: Brent A
authors.initials: BA
authors.lastname: Rupnow
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008969:Molecular Sequence Data; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D005231:Fatty Acids, Unsaturated; D034741:RNA, Small Interfering; C523776:SCD1 protein, human; C502659:SCD5 protein, human; D013230:Stearoyl-CoA Desaturase