Inhibition of fatty acid synthase induces endoplasmic reticulum stress in tumor cells

Cancer Res. 2007 Feb 1;67(3):1262-9. doi: 10.1158/0008-5472.CAN-06-1794.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Activating Transcription Factor 4 / biosynthesis
  • Activating Transcription Factor 4 / genetics
  • Animals
  • Cell Line, Tumor
  • DNA-Binding Proteins / biosynthesis
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Drug Interactions
  • Endoplasmic Reticulum / drug effects*
  • Endoplasmic Reticulum / enzymology*
  • Endoplasmic Reticulum / genetics
  • Endoplasmic Reticulum Chaperone BiP
  • Enzyme Inhibitors / pharmacology*
  • Eukaryotic Initiation Factor-2B / metabolism
  • Fatty Acid Synthases / antagonists & inhibitors*
  • Fatty Acid Synthases / biosynthesis
  • HT29 Cells
  • HeLa Cells
  • Heat-Shock Proteins / biosynthesis
  • Heat-Shock Proteins / genetics
  • Humans
  • Lactones / pharmacology
  • Male
  • Mice
  • Molecular Chaperones / biosynthesis
  • Molecular Chaperones / genetics
  • Nuclear Proteins / biosynthesis
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Orlistat
  • Phosphorylation
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / enzymology*
  • Regulatory Factor X Transcription Factors
  • Thapsigargin / pharmacology
  • Transcription Factor CHOP / biosynthesis
  • Transcription Factor CHOP / genetics
  • Transcription Factors
  • eIF-2 Kinase / metabolism

Substances

  • ATF4 protein, human
  • DDIT3 protein, human
  • DNA-Binding Proteins
  • Endoplasmic Reticulum Chaperone BiP
  • Enzyme Inhibitors
  • Eukaryotic Initiation Factor-2B
  • HSPA5 protein, human
  • Heat-Shock Proteins
  • Hspa5 protein, mouse
  • Lactones
  • Molecular Chaperones
  • Nuclear Proteins
  • Regulatory Factor X Transcription Factors
  • Transcription Factors
  • Activating Transcription Factor 4
  • Transcription Factor CHOP
  • Thapsigargin
  • Orlistat
  • Fatty Acid Synthases
  • PERK kinase
  • eIF-2 Kinase