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Proc Natl Acad Sci U S A. 2019 Jul 9;116(28):13943-13951. doi: 10.1073/pnas.1903297116. Epub 2019 Jun 20.

A structure-based mechanism of cisplatin resistance mediated by glutathione transferase P1-1.

Author information

1
Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy.
2
Australian Cancer Research Foundation Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, VIC 3065, Australia.
3
Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC 3010, Australia.
4
Department of Chemistry, National University of Singapore, 117506 Singapore.
5
Pediatric Gastroenterology and Liver Unit, Department of Pediatrics, Sapienza University of Rome, 00161 Rome, Italy.
6
Institut des Sciences et Ingénierie Chimiques, École Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
7
Australian Cancer Research Foundation Rational Drug Discovery Centre, St. Vincent's Institute of Medical Research, Fitzroy, VIC 3065, Australia; mparker@svi.edu.au paul.dyson@epfl.ch.
8
Institut des Sciences et Ingénierie Chimiques, École Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland mparker@svi.edu.au paul.dyson@epfl.ch.

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 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.

KEYWORDS:

cisplatin; drug resistance; glutathione transferase; protein crystallography; protein–ligand interactions

PMID:
31221747
DOI:
10.1073/pnas.1903297116
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