15‐Deoxy‐Δ<sup>12,14</sup>‐prostaglandin J<sub>2</sub> binds and inactivates STAT3 <i>via</i> covalent modification of cysteine 259 in H‐<i>Ras</i>‐transformed human breast epithelial cells
Su‐Jung Kim, Nam‐Chul Cho, Bitnara Han, Kyeojin Kim, Young‐Il Hahn, Kwang Pyo Kim, Young‐Ger Suh, Bu Young Choi, Hye‐Kyung Na, Young‐Joon Surh
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‐Δ 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.