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15-Deoxy-Delta(12,14)-prostaglandin J(2) binds and inactivates STAT3 via covalent modification of cysteine 259 in H-Ras-transformed human breast epithelial cells

Cited 3 time in Web of Science Cited 2 time in Scopus
Issue Date
2021-03
Citation
FEBS Letters, Vol.595 No.5, pp.604-622
Keywords
15-deoxy-Delta(12,14)-prostaglandin J(2);breast cancer;cyclopentenone prostaglandin;STAT3;alpha,beta-unsaturated carbonyl group;thiol modification
Abstract
Signal transducer and activator of transcription 3 (STAT3) has been considered as a potential target for development of anticancer therapeutics. Here, we report a novel mechanism by which the cyclopentenone prostaglandin, 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) functions as an allosteric inhibitor of STAT3. 15d-PGJ(2) inhibits phosphorylation, dimerization, nuclear translocation, and transcriptional activity of STAT3 in H-Ras-transformed human mammary epithelial cells (MCF10A-Ras) through the Michael addition reaction at cysteine 259 of STAT3. Comparative studies with 15d-PGJ(2) analogues reveal that both C12-C13 and C9-C10 double bonds conjugated to the carbonyl group in the cyclopentenone ring of 15d-PGJ(2) are essential for STAT3 binding. Antiproliferative and pro-apoptotic activities of 15d-PGJ(2) in MCF10A-Ras cells are attributable to covalent modification of STAT3 on Cys259, and mimic the effects induced by mutation of this amino acid.
ISSN
0014-5793
URI
https://hdl.handle.net/10371/178045
DOI
https://doi.org/10.1002/1873-3468.14040
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