15‐Deoxy‐Δ 12,14 ‐prostaglandin J 2 binds and inactivates STAT3 via covalent modification of cysteine 259 in H‐ Ras transformed human breast epithelial cells,FEBS Letters

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15‐Deoxy‐Δ 12,14 ‐prostaglandin J 2 binds and inactivates STAT3 via covalent modification of cysteine 259 in H‐ Ras transformed human breast epithelial cells
FEBS Letters ( IF 3.5 ) Pub Date : 2021-02-08 , DOI: 10.1002/1873-3468.14040
Su-Jung Kim ₁ , Nam-Chul Cho ₂ , Bitnara Han ₃ , Kyeojin Kim ₁ , Young-Il Hahn ₄ , Kwang Pyo Kim _{3,

5} , Young Ger Suh ₆ , Bu Young Choi ₇ , Hye-Kyung Na ₈ , Young-Joon Surh _{1,

4,

9}

Affiliation

Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Korea.
Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Korea.
Department of Applied Chemistry, Institute of Natural Science, Global Center for Pharmaceutical Ingredient Materials, Kyung Hee University, Yongin, Korea.
Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Korea.
Department of Biomedical Science and Technology, Kyung Hee Medical Science Research Institute, Kyung Hee University, Seoul, Korea.
College of Pharmacy, CHA University, Gyeonggi-do, Korea.
Department of Pharmaceutical Science and Engineering, School of Convergence Bioscience and Technology, Seowon University, Chungbuk, Korea.
Department of Food Science and Biotechnology, College of Knowledge Based Services Engineering, Sungshin Women's University, Seoul, Korea.
Cancer Research Institute, Seoul National University, Korea.

STAT3 has been considered as a potential target for development of anti-cancer 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. Anti-proliferative 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.

中文翻译：

15-Deoxy-Δ 12,14-前列腺素 J 2 通过 H-Ras 转化的人乳腺上皮细胞中半胱氨酸 259 的共价修饰结合并灭活 STAT3

STAT3 已被认为是开发抗癌疗法的潜在靶点。在这里，我们报告了环戊烯酮前列腺素,15-脱氧-Δ12,14-前列腺素 J2 (15d-PGJ2) 作为 STAT3 变构抑制剂发挥作用的新机制。15d-PGJ2 通过 STAT3 的半胱氨酸 259 的迈克尔加成反应抑制 H-Ras 转化的人乳腺上皮细胞 (MCF10A-Ras) 中 STAT3 的磷酸化、二聚化、核易位和转录活性。与 15d-PGJ2 类似物的比较研究表明，与 15d-PGJ2 环戊烯酮环中的羰基共轭的 C12-C13 和 C9-C10 双键对于 STAT3 结合是必不可少的。MCF10A-Ras 细胞中 15d-PGJ2 的抗增殖和促凋亡活性归因于 Cys259 上 STAT3 的共价修饰，

更新日期：2021-02-08

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