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: Long He, Jae Hyuk Jang, Hyun Gil Choi, Sun Mi Lee, Mei Hua Nan, Sook Jung Jeong, Zigang Dong, Yong Tae Kwon, Kyung Sang Lee, Ki Won Lee, Jong Kyeong Chung, Jong Seog Ahn, Bo Yeon Kim
• Journal: Molecular carcinogenesis (Mol Carcinog) Vol. 52 Issue 2 Pg. 85-93 (Feb 2013) ISSN: 1098-2744 [Electronic] United States
• PMID: 23335397 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Wiley Periodicals, Inc.

Chemical References

• 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

Topics

• Apoptosis (drug effects)
• DNA-Binding Proteins (genetics, 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, pharmacology)
• Transcription Factor CHOP (genetics, metabolism)
• Transcription Factors (genetics, metabolism)
• Up-Regulation (drug effects)
• X-Box Binding Protein 1