title: Oligomycin A enhances apoptotic effect of TRAIL through CHOP-mediated death receptor 5 expression.
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.
authors: Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon, South Korea.
authors: Long
authors: L
authors: He
authors: Jae Hyuk
authors: JH
authors: Jang
authors: Hyun Gil
authors: HG
authors: Choi
authors: Sun Mi
authors: SM
authors: Lee
authors: Mei Hua
authors: MH
authors: Nan
authors: Sook Jung
authors: SJ
authors: Jeong
authors: Zigang
authors: Z
authors: Dong
authors: Yong Tae
authors: YT
authors: Kwon
authors: Kyung Sang
authors: KS
authors: Lee
authors: Ki Won
authors: KW
authors: Lee
authors: Jong Kyeong
authors: JK
authors: Chung
authors: Jong Seog
authors: JS
authors: Ahn
authors: Bo Yeon
authors: BY
authors: Kim
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D004722:Endoribonucleases / Q000378:metabolism; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans; D008928:Mitochondria / Q000187:drug effects; D009840:Oligomycins / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D019154:Protein Splicing; D034741:RNA, Small Interfering / Q000235:genetics; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism* / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D000071717:X-Box Binding Protein 1
chemical_list: C497249:DDIT3 protein, human; D004268:DNA-Binding Proteins; D009840:Oligomycins; D034741:RNA, Small Interfering; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D000071701:Regulatory Factor X Transcription Factors; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C031004:oligomycin A; D051742:Transcription Factor CHOP; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases