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

Journal Article · · Proceedings of the National Academy of Sciences of the United States of America
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)
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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.

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
Citation Metrics:
Cited by: 57 works
Citation information provided by
Web of Science

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Cited By (3)

Transcriptomic Profiling Reveals AKR1C1 and AKR1C3 Mediate Cisplatin Resistance in Signet Ring Cell Gastric Carcinoma via Autophagic Cell Death journal November 2021
The Impact of Integrin-Mediated Matrix Adhesion on Cisplatin Resistance of W1 Ovarian Cancer Cells journal November 2019
A ratiometric fluorescent probe for detecting the endogenous biological signaling molecule superoxide anion and bioimaging during tumor treatment journal January 2020

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
cisplatin
drug resistance
glutathione transferase
protein crystallography
protein–ligand interactions