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

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

De Luca, Anastasia
•
Parker, Lorien J.
•
Ang, Wee Han  
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July 9, 2019
Proceedings Of The National Academy Of Sciences Of The United States Of America (PNAS)

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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13943.full.pdf

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http://purl.org/coar/version/c_970fb48d4fbd8a85

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