15-Deoxy-Δ12,14 -prostaglandin J2 binds and inactivates STAT3 via covalent modification of cysteine 259 in H-Ras-transformed human breast epithelial cells.
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-Δ12,14 -prostaglandin J2 (15d-PGJ2 ) functions as an allosteric inhibitor of STAT3. 15d-PGJ2 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-PGJ2 analogues reveal that both C12-C13 and C9-C10 double bonds conjugated to the carbonyl group in the cyclopentenone ring of 15d-PGJ2 are essential for STAT3 binding. Antiproliferative and pro-apoptotic activities of 15d-PGJ2 in MCF10A-Ras cells are attributable to covalent modification of STAT3 on Cys259, and mimic the effects induced by mutation of this amino acid.
['Kim|Su-Jung|SJ|0000-0002-3636-0644', 'Cho|Nam-Chul|NC|0000-0002-6735-1302', 'Han|Bitnara|B|0000-0002-3981-9684', 'Kim|Kyeojin|K|0000-0002-2507-9427', 'Hahn|Young-Il|YI|0000-0003-2903-9251', 'Kim|Kwang Pyo|KP|0000-0003-0095-3787', 'Suh|Young Ger|YG|0000-0003-1799-8607', 'Choi|Bu Young|BY|0000-0001-8698-5880', 'Na|Hye-Kyung|HK|0000-0003-0460-2810', 'Surh|Young-Joon|YJ|0000-0001-8310-1795']
D000595:Amino Acid Sequence D000970:Antineoplastic Agents D017209:Apoptosis D002461:Cell Line, Transformed D049109:Cell Proliferation D003545:Cysteine D004847:Epithelial Cells D015972:Gene Expression Regulation, Neoplastic D006801:Humans D042361:Mammary Glands, Human D010766:Phosphorylation D015230:Prostaglandin D2 D011485:Protein Binding D055503:Protein Multimerization D021381:Protein Transport D016283:Proto-Oncogene Proteins p21(ras) D050796:STAT3 Transcription Factor D013329:Structure-Activity Relationship D014158:Transcription, Genetic
STAT3 cyclopentenone prostaglandin 15-deoxy-∆12,14-prostaglandin J2 breast cancer thiol modification α,β-unsaturated carbonyl group