title: Inhibition of fatty acid synthase induces endoplasmic reticulum stress in tumor cells.
abstract: Fatty acid synthase (FAS), the cellular enzyme that synthesizes palmitate, is expressed at high levels in tumor cells and is vital for their survival. Through the synthesis of palmitate, FAS primarily drives the synthesis of phospholipids in tumor cells. In this study, we tested the hypothesis that the FAS inhibitors induce endoplasmic reticulum (ER) stress in tumor cells. Treatment of tumor cells with FAS inhibitors induces robust PERK-dependent phosphorylation of the translation initiation factor eIF2alpha and concomitant inhibition of protein synthesis. PERK-deficient transformed mouse embryonic fibroblasts and HT-29 colon carcinoma cells that express a dominant negative PERK (DeltaC-PERK) are hypersensitive to FAS inhibitor-induced cell death. Pharmacologic inhibition of FAS also induces the processing of X-box binding protein-1, indicating that the IRE1 arm of the ER stress response is activated when FAS is inhibited. Induction of ER stress is further confirmed by the increased expression of the ER stress-regulated genes CHOP, ATF4, and GRP78. FAS inhibitor-induced ER stress is activated prior to the detection of caspase 3 and PARP cleavage, primary indicators of cell death, whereas orlistat-induced cell death is rescued by coincubation with the global translation inhibitor cycloheximide. Lastly, FAS inhibitors cooperate with the ER stress inducer thapsigargin to enhance tumor cell killing. These results provide the first evidence that FAS inhibitors induce ER stress and establish an important mechanistic link between FAS activity and ER function.
authors.affiliation: Department of Cancer Biology, Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Joy L
authors.initials: JL
authors.lastname: Little
authors.forename: Frances B
authors.initials: FB
authors.lastname: Wheeler
authors.forename: Diane R
authors.initials: DR
authors.lastname: Fels
authors.forename: Constantinos
authors.initials: C
authors.lastname: Koumenis
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Kridel
mesh_terms: D051701:Activating Transcription Factor 4 / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D004347:Drug Interactions; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D000091342:Endoplasmic Reticulum Chaperone BiP; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020717:Eukaryotic Initiation Factor-2B / Q000378:metabolism; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D019073:HT29 Cells; D006367:HeLa Cells; D006360:Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007783:Lactones / Q000494:pharmacology; D008297:Male; D051379:Mice; D018832:Molecular Chaperones / Q000096:biosynthesis / Q000235:genetics; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D000077403:Orlistat; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D000071701:Regulatory Factor X Transcription Factors; D019284:Thapsigargin / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D051701:Activating Transcription Factor 4; D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D004791:Enzyme Inhibitors; D020717:Eukaryotic Initiation Factor-2B; D064429:Fatty Acid Synthases; D006360:Heat-Shock Proteins; D007783:Lactones; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D000077403:Orlistat; D000071701:Regulatory Factor X Transcription Factors; D019284:Thapsigargin; D051742:Transcription Factor CHOP; D014157:Transcription Factors; D019892:eIF-2 Kinase; C497109:ATF4 protein, human; C497249:DDIT3 protein, human; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse