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

De Luca, Anastasia; Parker, Lorien J.; Ang, Wee Han; Rodolfo, Carlo; Gabbarini, Valentina; Hancock, Nancy C.; Palone, Francesca; Mazzetti, Anna P.; Menin, Laure; Morton, Craig J.; Parker, Michael W.; Lo Bello, Mario; Dyson, Paul J.

doi:10.1073/pnas.1903297116

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

Journal Article · 20 June 2019 · Proceedings of the National Academy of Sciences of the United States of America

DOI: https://doi.org/10.1073/pnas.1903297116 · OSTI ID:1545870

^[1]; Parker, Lorien J. ^[2]; Ang, Wee Han ^[3]; Rodolfo, Carlo ^[1]; Gabbarini, Valentina ^[1]; Hancock, Nancy C. ^[4]; Palone, Francesca ^[1]; Mazzetti, Anna P. ^[1]; Menin, Laure ^[5];

^[2];

^[2]; Lo Bello, Mario ^[1];

^[5]

Univ. of Rome Tor Vergata (Italy)
St. Vincent’s Inst. of Medical Research, Fitzroy, VIC (Australia); Univ. of Melbourne (Australia)
Univ. of Singapore (Singapore)
St. Vincent’s Inst. of Medical Research, Fitzroy, VIC (Australia)
Ecole Polytechnique Federale Lausanne (Switzlerland)

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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

OSTI ID:: 1545870

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, Issue 28; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 66 works

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