Silencing of the STAT3 signaling pathway reverses the inherent and induced chemoresistance of human ovarian cancer cells
Silencing of the STAT3 signaling pathway reverses the inherent and induced chemoresistance of human ovarian cancer cells
复制标题
STAT3 信号通路的沉默可逆转人卵巢癌细胞固有的和诱导的化疗耐药性。
DOI：
10.1016/j.bbrc.2013.04.087
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发表时间：
2013-05-31
影响因子：
3.1
通讯作者：
Gao, Qinglei
中科院分区：
文献类型：
--
作者：
Han, Zhiqiang;Feng, Jing;Gao, Qinglei
卵巢癌是女性妇科癌症死亡的主要原因。尽管铂类化疗是人类卵巢癌的一线治疗方法，但耐药性仍然是成功治疗的主要障碍，目前还没有批准的分子靶向治疗。最近的证据表明，信号转导和转录激活因子-3（STAT 3）是化疗耐药的决定因素，并与许多实体肿瘤的复发有关。在这项研究中，我们证明了高水平的pSTAT 3与人卵巢癌细胞的化疗耐药性相关。通过siRNA技术靶向STAT 3显著增强顺铂诱导的高表达pSTAT 3的顺铂耐药卵巢癌细胞的凋亡。白细胞介素-6（IL-6）可诱导顺铂敏感的卵巢癌细胞中STAT 3活化，并导致对顺铂的保护作用。STAT 3 siRNA处理还阻断了IL-6诱导的STAT 3磷酸化，导致IL-6的抗凋亡活性减弱。我们发现顺铂与STAT 3、siRNA联合应用导致线粒体膜电位下降，Bcl-xL和Bcl-2的表达减弱，细胞色素C的释放和Bax的表达增加。综上所述，这些结果表明，STAT 3的药理学抑制可能是一种有前途的治疗策略，用于管理卵巢癌的化疗耐药性。(c)2013 Elsevier Inc. All rights reserved.
Ovarian cancer is the leading cause of gynecologic cancer deaths among women. Although platinum-based chemotherapy is the first-line treatment for human ovarian cancer, chemoresistance remains a major obstacle to successful treatment, and there are currently no approved molecularly targeted therapies. Recent evidence indicates that signal transducer and activator of transcription-3 (STAT3) is a determinant of chemoresistance and is related to tumor recurrence in a large number of solid malignancies. In this study, we demonstrated that high levels of pSTAT3 were associated with chemoresistance in human ovarian cancer cells. Targeting STAT3 by siRNA technology markedly enhanced cisplatin-induced apoptosis in cisplatin-resistant ovarian cancer cells that expressed a high level of pSTAT3. Interleukin-6 (IL-6) could induce STAT3 activation in cisplatin-sensitive ovarian cancer cells and led to protection against cisplatin. The STAT3 siRNA treatment also blocked IL-6-induced STAT3 phosphorylation, resulting in the attenuation of the anti-apoptotic activity of IL-6. We found that the combination of cisplatin and STAT3, siRNA resulted in the collapse of the mitochondrial membrane potential, attenuated the expression of Bcl-xL and Bcl-2, and increased the release of cytochrome C and expression of Bax. Taken together, these results suggest that the pharmacological inhibition of STAT3 may be a promising therapeutic strategy for the management of chemoresistance in ovarian cancer. (c) 2013 Elsevier Inc. All rights reserved.