3-O-(Z)-coumaroyloleanolic acid overcomes Cks1b-induced chemoresistance in lung cancer by inhibiting Hsp90 and MEK pathways
3-O-(Z)-coumaroyloleanolic acid overcomes Cks1b-induced chemoresistance in lung cancer by inhibiting Hsp90 and MEK pathways
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DOI：
10.1016/j.bcp.2017.03.007
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发表时间：
2017-07-01
影响因子：
5.8
通讯作者：
Zhou, Yi
中科院分区：
文献类型：
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作者：
Wang, He;Sun, Mingna;Zhou, Yi
CDC28蛋白激酶调控亚基1 （Cks1）的表达在转录和翻译后水平受到严格调控，Cks1是细胞周期蛋白依赖性激酶的接头。Cks1表达的增加已被证明可归因于癌症进展、化疗耐药和化疗敏感性。在这里，我们报道了Cks1b在人肺癌细胞（Cks1b- oe）中的异位过表达（Cks1b- oe）通过独立于其典型的Skp2-p27途径的机制诱导细胞对顺铂（CDDP）和阿霉素（DOX）的化疗耐药。利用shRNA和选择性抑制剂进一步解剖发现，Hsp90和MEK1/2是cks1b诱导的化疗耐药的非规范通路的关键组分。有趣的是，通过抑制Hsp90或MEK1/2，化疗耐药的Cks1b- oe细胞对CDDP和DOX的再敏化，产生了相似程度的抗肿瘤活性，这表明Hsp90和MEK1/2都是Cks1b诱导化疗耐药所必需的。此外，3-O-(Z)- coumaroyl齐墩果酸（3-COA）是苦楝叶齐墩果酸的有效成分，已被证明对A549肺癌细胞具有抗肿瘤活性，在体外和体内实验中，对Cks1b-OE细胞和复发性原发性人肺癌细胞单独或与CDDP或DOX联合使用时，其抗肿瘤活性与Hsp90特异性抑制剂PU-H71相似，表明3-COA是一种新型的Hsp90抑制剂。我们的数据首次报道了Cks1b在肺癌细胞中通过Hsp90和MEK1/2通路产生化疗耐药，并鉴定出3-COA作为一种潜在的抗肿瘤药物用于化疗耐药肺癌的临床治疗。(C) 2017爱思唯尔公司版权所有。
Expression of CDC28 protein kinase regulatory subunit 1 (Cks1), an adaptor for cyclin-dependent kinases, is tightly regulated at transcriptional and posttranslational levels. Increased expression of Cks1 has been documented to be attributable to cancer progression, chemoresistance, and chemosensitivity. Here we report that ectopic overexpression of Cks1b in human lung cancer cells (Cks1b-OE) induces chemoresistance of the cells to cisplatin (CDDP) and doxorubicin (DOX) through mechanisms independent of its canonical Skp2-p27 pathway. Further dissection with application of shRNA and selective inhibitors reveals that Hsp90 and MEK1/2 are the critical components of the non-canonical pathways responsible for the Cks1b-induced chemoresistance. Interestingly, inhibition of either Hsp90 or MEK1/2 rendered a similar magnitude of antitumor activity by resensitization of the chemoresistant Cks1b-OE cells to CDDP and DOX, suggesting that both Hsp90 and MEK1/2 are essential to Cks1b for induction of chemoresistance. Moreover, 3-O-(Z)-coumaroyloleanolic acid (3-COA), an active ingredient of oleanolic acid in the leaves of E. oldhamii Maxim, that has been shown to have antitumor activity against A549 lung cancer cells, mimicked PU-H71, a Hsp90-specific inhibitor, in antitumor activity when used alone or in combination with CDDP or DOX in Cks1b-OE cells and recurrent primary human lung cancer cells both in vitro and in vivo, suggesting that 3-COA is a novel Hsp90 inhibitor. Our data report for the first time that Cks1b employs Hsp90 and MEK1/2 pathways in lung cancer cells to develop chemoresistance and identify 3-COA as a potential antitumor drug for clinical treatment of chemoresistant lung cancer. (C) 2017 Elsevier Inc. All rights reserved.