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ABT-737 通过 JNK 信号通路诱导 Bim 表达及其对 HeLa 细胞辐射敏感性的影响。

ABT-737 induces Bim expression via JNK signaling pathway and its effect on the radiation sensitivity of HeLa cells.

机构信息

Gynecology Department, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.

出版信息

PLoS One. 2012;7(12):e52483. doi: 10.1371/journal.pone.0052483. Epub 2012 Dec 20.

Abstract

ABT-737 is a BH3 mimetic small molecule inhibitor that can effectively inhibit the activity of antiapoptotic Bcl-2 family proteins including Bcl2, Bcl-xL and Bcl-w, and further enhances the effect of apoptosis by activating the proapoptotic proteins (t-Bid, Bad, Bim). In this study, we demonstrate that ABT-737 improved the radiation sensitivity of cervical cancer HeLa cells and thereby provoked cell apoptosis. Our results show that ABT-737 inhibited HeLa cell proliferation and activated JNK and its downstream target c-Jun, which caused the up-regulation of Bim expression. Blockade of JNK/c-Jun signaling pathway resulted in significant down-regulation of ABT-737-induced Bim mRNA and protein expression level. Also, ABT-737 could evoke the Bim promoter activity, and enhance the radiation sensitivity of HeLa cells via JNK/c-Jun and Bim signaling pathway. Our data imply that combination of ABT-737 and conventional radiation therapy might represent a highly effective therapeutic approach for future treatment of cervical cancer.

摘要

ABT-737 是一种 BH3 模拟小分子抑制剂,能有效抑制包括 Bcl2、Bcl-xL 和 Bcl-w 在内的抗凋亡 Bcl-2 家族蛋白的活性,同时通过激活促凋亡蛋白(t-Bid、Bad、Bim)进一步增强凋亡效果。在本研究中,我们证明 ABT-737 提高了宫颈癌 HeLa 细胞的辐射敏感性,从而引发细胞凋亡。结果表明,ABT-737 抑制 HeLa 细胞增殖并激活 JNK 及其下游靶标 c-Jun,导致 Bim 表达上调。阻断 JNK/c-Jun 信号通路会导致 ABT-737 诱导的 Bim mRNA 和蛋白表达水平显著下调。此外,ABT-737 可激活 Bim 启动子活性,并通过 JNK/c-Jun 和 Bim 信号通路增强 HeLa 细胞的辐射敏感性。数据表明,ABT-737 与常规放射治疗相结合可能代表未来治疗宫颈癌的一种高效治疗方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c7d2/3527555/a7225c41cb23/pone.0052483.g001.jpg

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