期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 116, 期 28, 页码 13943-13951出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1903297116
关键词
cisplatin; drug resistance; glutathione transferase; protein crystallography; protein-ligand interactions
资金
- National Centre of Competence in Research in Chemical Biology (Switzerland)
- Australian Synchrotron Research Program
- Commonwealth of Australia under the Major National Research Facilities Program
- US Department of Energy, Basic Energy Sciences, Office of Energy Research
- Australian Research Council
- Australian Cancer Research Foundation
- Minister of Instruction, University and Research
- Genesys SpA
- Victorian Government Operational Infrastructure Support Scheme
- National Health and Medical Research Council of Australia (NHMRC) Dora Lush Scholarship
- International Centre for Diffraction Data Crystallography Scholarship
Cisplatin [cis-diamminedichloroplatinum(II) (cis-DDP)] is one of the most successful anticancer agents effective against a wide range of solid tumors. However, its use is restricted by side effects and/or by intrinsic or acquired drug resistance. Here, we probed the role of glutathione transferase (GST) P1-1, an antiapoptotic protein often overexpressed in drug-resistant tumors, as a cis-DDP-binding protein. Our results show that cis DDP is not a substrate for the glutathione (GSH) transferase activity of GST P1-1. Instead, GST P1-1 sequesters and inactivates cisplatin with the aid of 2 solvent-accessible cysteines, resulting in protein subunits cross-linking, while maintaining its GSH-conjugation activity. Furthermore, it is well known that GST P1-1 binding to the c-Jun N-terminal kinase (JNK) inhibits JNK phosphorylation, which is required for downstream apoptosis signaling. Thus, in turn, GST P1-1 overexpression and Pt-induced subunit cross-linking could modulate JNK apoptotic signaling, further confirming the role of GST P1-1 as an antiapoptotic protein.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据