title: Inhibition of stearoyl-CoA desaturase 1 expression induces CHOP-dependent cell death in human cancer cells.
abstract: BACKGROUND
  Cancer cells present a sustained de novo fatty acid synthesis with an increase of saturated and monounsaturated fatty acid (MUFA) production. This change in fatty acid metabolism is associated with overexpression of stearoyl-CoA desaturase 1 (Scd1), which catalyses the transformation of saturated fatty acids into monounsaturated fatty acids (e.g., oleic acid). Several reports demonstrated that inhibition of Scd1 led to the blocking of proliferation and induction of apoptosis in cancer cells. Nevertheless, mechanisms of cell death activation remain to be better understood.
  
  
  RESULTS
  In this study, we demonstrated that Scd1 extinction by siRNA triggered abolition of de novo MUFA synthesis in cancer and non-cancer cells. Scd1 inhibition-activated cell death was only observed in cancer cells with induction of caspase 3 activity and PARP-cleavage. Exogenous supplementation with oleic acid did not reverse the Scd1 ablation-mediated cell death. In addition, Scd1 depletion induced unfolded protein response (UPR) hallmarks such as Xbp1 mRNA splicing, phosphorylation of eIF2α and increase of CHOP expression. However, the chaperone GRP78 expression, another UPR hallmark, was not affected by Scd1 knockdown in these cancer cells indicating a peculiar UPR activation. Finally, we showed that CHOP induction participated to cell death activation by Scd1 extinction. Indeed, overexpression of dominant negative CHOP construct and extinction of CHOP partially restored viability in Scd1-depleted cancer cells.
  
  
  CONCLUSIONS
  These results suggest that inhibition of de novo MUFA synthesis by Scd1 extinction could be a promising anti-cancer target by inducing cell death through UPR and CHOP activation.
authors.affiliation: Université de Bourgogne, Centre de Recherche INSERM Lipides, Nutrition, Cancer UMR866, Dijon, France.
authors.forename: Mélaine
authors.initials: M
authors.lastname: Minville-Walz
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Pierre
authors.forename: Laurent
authors.initials: L
authors.lastname: Pichon
authors.forename: Sandrine
authors.initials: S
authors.lastname: Bellenger
authors.forename: Cécile
authors.initials: C
authors.lastname: Fèvre
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bellenger
authors.forename: Christian
authors.initials: C
authors.lastname: Tessier
authors.forename: Michel
authors.initials: M
authors.lastname: Narce
authors.forename: Mickaël
authors.initials: M
authors.lastname: Rialland
mesh_terms: D017209:Apoptosis; D016923:Cell Death; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000378:metabolism*; D019301:Oleic Acid / Q000737:chemistry; D034741:RNA, Small Interfering / Q000378:metabolism; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D051742:Transcription Factor CHOP / Q000378:metabolism*
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; D005227:Fatty Acids; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D034741:RNA, Small Interfering; D051742:Transcription Factor CHOP; D019301:Oleic Acid; D013230:Stearoyl-CoA Desaturase