ABT-737 induces Bim expression via JNK signaling pathway and its effect on the radiation sensitivity of HeLa cells.

Abstract

ABT-737 is a BH3 mimetic small molecule inhibitor that can effectively inhibit the activity of antiapoptotic Bcl-2 family proteins including Bcl2, Bcl-xL and Bcl-w, and further enhances the effect of apoptosis by activating the proapoptotic proteins (t-Bid, Bad, Bim). In this study, we demonstrate that ABT-737 improved the radiation sensitivity of cervical cancer HeLa cells and thereby provoked cell apoptosis. Our results show that ABT-737 inhibited HeLa cell proliferation and activated JNK and its downstream target c-Jun, which caused the up-regulation of Bim expression. Blockade of JNK/c-Jun signaling pathway resulted in significant down-regulation of ABT-737-induced Bim mRNA and protein expression level. Also, ABT-737 could evoke the Bim promoter activity, and enhance the radiation sensitivity of HeLa cells via JNK/c-Jun and Bim signaling pathway. Our data imply that combination of ABT-737 and conventional radiation therapy might represent a highly effective therapeutic approach for future treatment of cervical cancer.

• Authors: Huan Wang, Yue-Bo Yang, Hui-Min Shen, Jian Gu, Tian Li, Xiao-Mao Li
• Journal: PloS one (PLoS One) Vol. 7 Issue 12 Pg. e52483 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 23285061 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ABT-737
• Apoptosis Regulatory Proteins
• BCL2L11 protein, human
• Bcl-2-Like Protein 11
• Biphenyl Compounds
• Membrane Proteins
• Nitrophenols
• Piperazines
• Proto-Oncogene Proteins
• Proto-Oncogene Proteins c-jun
• RNA, Messenger
• Sulfonamides

Topics

• Apoptosis (drug effects, genetics, radiation effects)
• Apoptosis Regulatory Proteins (genetics, metabolism)
• Bcl-2-Like Protein 11
• Biphenyl Compounds (pharmacology)
• Cell Proliferation (drug effects, radiation effects)
• Drug Screening Assays, Antitumor
• Enzyme Activation (drug effects, radiation effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• HeLa Cells
• Humans
• MAP Kinase Signaling System (drug effects, genetics, radiation effects)
• Membrane Proteins (genetics, metabolism)
• Nitrophenols (pharmacology)
• Piperazines (pharmacology)
• Promoter Regions, Genetic (genetics)
• Proto-Oncogene Proteins (genetics, metabolism)
• Proto-Oncogene Proteins c-jun (metabolism)
• RNA, Messenger (genetics, metabolism)
• Radiation
• Radiation Tolerance (drug effects, genetics, radiation effects)
• Sulfonamides (pharmacology)