Abrogation of constitutive Stat3 activity circumvents cisplatin resistant ovarian cancer
Abrogation of constitutive Stat3 activity circumvents cisplatin resistant ovarian cancer
复制标题
消除 Stat3 的组成型活性可避免顺铂耐药的卵巢癌。
DOI：
10.1016/j.canlet.2013.08.022
复制
发表时间：
2013-12-01
期刊：
影响因子：
9.7
通讯作者：
Gao, Qinglei
中科院分区：
文献类型：
--
作者：
Ji, Teng;Gong, Danni;Gao, Qinglei
本研究的目的是探讨STAT3在顺铂耐药卵巢癌中的作用。首次证实在顺铂耐药的卵巢癌细胞系中检测到高活性的STAT3。为了提供证据支持磷酸化的STAT3表达可能促进顺铂耐药的假设，异位STAT3通过部分消除STAT3的IL-6刺激表达，而不是通过特定的siRNA下调STAT3的表达，从而恢复顺铂对卵巢癌细胞的敏感性。从顺铂耐药患者获得的卵巢癌临床肿瘤标本进一步证实了这一假设。基于这些前提，STAT3的有效小分子抑制剂Stattic[1]被用来抑制STAT3的激活。本文提供的数据表明，STATTIC通过显著降低抗凋亡蛋白Bcl2、BclX-L、Survivin蛋白和磷酸化Akt的水平，恢复了化疗耐药卵巢癌对顺铂的敏感性。与这些观察一致，这项实验首次证明了他汀类药物规避了体内异种移植卵巢癌对顺铂的耐药性。总之，这些发现强调了STAT3在卵巢癌顺铂耐药中的重要性，并为临床评估可能绕过化疗耐药卵巢癌患者顺铂耐药的生物修饰剂提供了进一步的推动力。(C)2013爱思唯尔爱尔兰有限公司。保留所有权利。
The aim of the present study was to investigate the role of Stat3 in cisplatin resistant ovarian cancer. It was first demonstrated that higher activated Stat3 was detected in cisplatin-resistant ovarian cancer cell lines. To provide evidence that supported the hypothesis that phosphorylated-Stat3 expression may promote cisplatin resistance, ectopic Stat3 was expressed by IL-6 stimulation that partially abrogates Stat3, as opposed to the knock-down of Stat3 by specific siRNA that restores cisplatin sensitivity against ovarian cancer cells. This hypothesis was further confirmed by clinical tumor specimens of ovarian cancer obtained from patients with cisplatin-resistance. Based on these premises, Stattic [1], an effective small molecular inhibitor of Stat3, was used to inhibit Stat3 activation. The data presented here show that Stattic restored the sensitivity to cisplatin in chemoresistant ovarian cancer by significant reductions in the expression of the anti-apoptosis protein Bcl-2, Bcl-X-L, Survivin protein and phosphorylated-Akt levels. Consistent with these observations, this experiment demonstrated the first evidence of Stattic circumvented cisplatin resistance of orthotopic xenograft ovarian cancer in vivo. Altogether, these findings emphasize the importance of Stat3 in cisplatin resistance in ovarian cancer and provide a further impetus to clinically evaluate biological modifiers that may circumvent cisplatin resistance in patients with chemoresistant ovarian cancer. (c) 2013 Elsevier Ireland Ltd. All rights reserved.