Abstract
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 acis-DDP–binding protein. Our results show thatcis-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.
Funder
Australian Research Council
Australian Cancer Research Foundation
National Health and Medical Research Council of Australia (NHMRC) Dora Lush Scholarship
Ministero dell'Istruzione, dell'Università e della Ricerca
Genesys SpA
National Centre of Competence in Research (NCCR) in Chemical Biology
International Centre for Diffraction Data Crystallography Scholarship
Publisher
Proceedings of the National Academy of Sciences
Cited by
75 articles.
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