Oligomycin A enhances apoptotic effect of TRAIL through CHOP-mediated death receptor 5 expression

Mol Carcinog. 2013 Feb;52(2):85-93. doi: 10.1002/mc.21831. Epub 2011 Nov 15.

Abstract

Development of resistance to TNF-related apoptosis-inducing ligand (TRAIL) in tumor cells is one of the important problems in cancer treatment. Despite the previous report demonstrating that oligomycin suppressed TNF-induced apoptosis, in our screening of small molecules enhancing cancer cell death to TRAIL, oligomycin A (OMA) was found to enhance TRAIL-induced apoptosis in HeLa cells. CCAAT/enhancer-binding protein homologous protein (CHOP) was found to directly bind to death receptor 5 (DR5) promoter through endoplasmic reticulum stress (ER-stress) signaling and sensitize the cells to TRAIL. Among ER-stress associated proteins, OMA triggered the inositol-requiring enzyme 1 (IRE1) signaling pathway, leading to X-binding protein 1 (XBP1) splicing, CHOP expression and DR5 upregulation. In contrast, small-interfering RNA (siRNA) of CHOP reduced the number of apoptotic cells in response to the co-treatment of TRAIL and OMA. Collectively, our data suggest that OMA enhances apoptotic death of cervical cancer cells to TRAIL through upregulation of CHOP-mediated DR5 expression following ER-stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Endoplasmic Reticulum Stress
  • Endoribonucleases / metabolism
  • HeLa Cells / drug effects
  • Humans
  • Mitochondria / drug effects
  • Oligomycins / pharmacology*
  • Promoter Regions, Genetic / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Protein Splicing
  • RNA, Small Interfering / genetics
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism*
  • Regulatory Factor X Transcription Factors
  • Signal Transduction / drug effects
  • TNF-Related Apoptosis-Inducing Ligand / metabolism*
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology
  • Transcription Factor CHOP / genetics
  • Transcription Factor CHOP / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Up-Regulation / drug effects
  • X-Box Binding Protein 1

Substances

  • DDIT3 protein, human
  • DNA-Binding Proteins
  • Oligomycins
  • RNA, Small Interfering
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Regulatory Factor X Transcription Factors
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Transcription Factors
  • X-Box Binding Protein 1
  • XBP1 protein, human
  • oligomycin A
  • Transcription Factor CHOP
  • ERN1 protein, human
  • Protein Serine-Threonine Kinases
  • Endoribonucleases