Journal
FEBS LETTERS
Volume 595, Issue 5, Pages 604-622Publisher
WILEY
DOI: 10.1002/1873-3468.14040
Keywords
15-deoxy-Delta(12,14)-prostaglandin J(2); breast cancer; cyclopentenone prostaglandin; STAT3; alpha,beta-unsaturated carbonyl group; thiol modification
Funding
- National Research Foundation of Korea [370C-20090062, 370C-20120085]
- BK21 FOUR Program [5120200513755]
- Global Core Research Center (GCRC) grant from the National Research Foundation of Korea [2011-003-0001]
- GRRC program of Gyeonggi province [GRRC-Kyung Hee 2018 (B03)]
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The cyclopentenone prostaglandin 15d-PGJ2 functions as an allosteric inhibitor of STAT3 by covalently modifying STAT3 on Cys259, inhibiting its activity in MCF10A-Ras cells. This results in antiproliferative and pro-apoptotic effects similar to mutation of this amino acid.
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.
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