title: Silencing of the STAT3 signaling pathway reverses the inherent and induced chemoresistance of human ovarian cancer cells.
abstract: 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.
authors.affiliation: Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, PR China.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Han
authors.forename: Jing
authors.initials: J
authors.lastname: Feng
authors.forename: Zhenya
authors.initials: Z
authors.lastname: Hong
authors.forename: Lijuan
authors.initials: L
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Shujie
authors.initials: S
authors.lastname: Liao
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Wang
authors.forename: Teng
authors.initials: T
authors.lastname: Ji
authors.forename: Shixuan
authors.initials: S
authors.lastname: Wang
authors.forename: Ding
authors.initials: D
authors.lastname: Ma
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Qinglei
authors.initials: Q
authors.lastname: Gao
mesh_terms: D000970:Antineoplastic Agents; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D020868:Gene Silencing; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D002945:Cisplatin