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

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.

Authors:
ORCiD logo [1];  [2];  [3];  [1];  [1];  [4];  [1];  [1];  [5]; ORCiD logo [2]; ORCiD logo [2];  [1]; ORCiD logo [5]
  1. Univ. of Rome Tor Vergata (Italy)
  2. St. Vincent’s Inst. of Medical Research, Fitzroy, VIC (Australia); Univ. of Melbourne (Australia)
  3. Univ. of Singapore (Singapore)
  4. St. Vincent’s Inst. of Medical Research, Fitzroy, VIC (Australia)
  5. Ecole Polytechnique Federale Lausanne (Switzlerland)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
OSTI Identifier:
1545870
Resource Type:
Accepted Manuscript
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 116; Journal Issue: 28; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; cisplatin; drug resistance; glutathione transferase; protein crystallography; protein–ligand interactions

Citation Formats

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, and Dyson, Paul J. A structure-based mechanism of cisplatin resistance mediated by glutathione transferase P1-1. United States: N. p., 2019. Web. doi:10.1073/pnas.1903297116.
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. A structure-based mechanism of cisplatin resistance mediated by glutathione transferase P1-1. United States. doi:10.1073/pnas.1903297116.
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, and Dyson, Paul J. Thu . "A structure-based mechanism of cisplatin resistance mediated by glutathione transferase P1-1". United States. doi:10.1073/pnas.1903297116.
@article{osti_1545870,
title = {A structure-based mechanism of cisplatin resistance mediated by glutathione transferase P1-1},
author = {De Luca, Anastasia and Parker, Lorien J. and Ang, Wee Han and Rodolfo, Carlo and Gabbarini, Valentina and Hancock, Nancy C. and Palone, Francesca and Mazzetti, Anna P. and Menin, Laure and Morton, Craig J. and Parker, Michael W. and Lo Bello, Mario and Dyson, Paul J.},
abstractNote = {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.},
doi = {10.1073/pnas.1903297116},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 28,
volume = 116,
place = {United States},
year = {2019},
month = {6}
}

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