title: The telomere/telomerase binding factor PinX1 regulates paclitaxel sensitivity depending on spindle assembly checkpoint in human cervical squamous cell carcinomas.
abstract: Paclitaxel is a main ingredient in the combination chemotherapy treatment of advanced human cervical squamous cell carcinomas. We investigated the roles and underlying molecular mechanisms of PinX1 in cervical squamous cell carcinomas (CSCC) cells response to paclitaxel and its clinical significances. The expression dynamics of PinX1 was first examined by immunohistochemistry in 122 advanced CSCC patients treated with cisplatin/paclitaxel chemotherapy. The expression of PinX1 was significantly associated with the effects of cisplatin/paclitaxel chemotherapy in advanced CSCCs (P<0.05). High expression of PinX1 correlated with CSCC's response to cisplatin/paclitaxel chemotherapy, and was an independent predictor of shortened survival (P<0.05). A series of in vivo and in vitro assays were performed to elucidate the function of PinX1 on CSCC cells chemosensitivity to paclitaxel and underlying mechanisms. In CSCC cells, the levels of PinX1 were only associated with the cytotoxicity and sensitivity of paclitaxel, in which knockdown of PinX1 dramatically enhanced paclitaxel cytotoxicity, whereas the reestablishment of PinX1 levels substantially reduced the paclitaxel-induced killing effect. In addition, we identified that the ability of PinX1 to stabilize the tension between sister kinetochores and maintain the spindle assembly checkpoint was the main reason CSCC cells undergo apoptosis when treated with paclitaxel, and further studies demonstrated that shortened distance between sisters kinetochores by nocodazole confers upon PinX1-replenished cells a sensitivity to the death inducing paclitaxel effects. Furthermore, our study of CSCC cells xenografts in nude mice confirmed the role of PinX1 in paclitaxel sensitivity in vivo. Our data reveal that PinX1 could be used as a novel predictor for CSCC patient response to paclitaxel, and the role of PinX1-mediated paclitaxel sensitivity might represent a new direction for the development of a new generation of microtubule drugs.
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: Xiao-Peng
authors.initials: XP
authors.lastname: Tian
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Qian
authors.affiliation: Department of Radiation Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: Li-Ru
authors.initials: LR
authors.lastname: He
authors.affiliation: Department of Gynecology, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: He
authors.initials: H
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: Shi-Juan
authors.initials: SJ
authors.lastname: Mai
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: Chang-Peng
authors.initials: CP
authors.lastname: Li
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: Xiao-Xia
authors.initials: XX
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China; Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: Mu-Yan
authors.initials: MY
authors.lastname: Cai
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: Yi-Ji
authors.initials: YJ
authors.lastname: Liao
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: Hsiang-fu
authors.initials: HF
authors.lastname: Kung
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Zeng
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China. Electronic address: xiedan@sysucc.org.cn.
authors.forename: Dan
authors.initials: D
authors.lastname: Xie
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D018797:Cell Cycle Proteins; D002945:Cisplatin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D005260:Female; D006367:HeLa Cells; D006801:Humans; D018386:Kinetochores / Q000187:drug effects / Q000378:metabolism; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects*; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage; D034622:RNA Interference; D008941:Spindle Apparatus / Q000187:drug effects* / Q000378:metabolism; D016019:Survival Analysis; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D016896:Treatment Outcome; D050257:Tubulin Modulators / Q000008:administration & dosage; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D018797:Cell Cycle Proteins; C440808:PINX1 protein, human; D050257:Tubulin Modulators; D025521:Tumor Suppressor Proteins; D019098:Telomerase; D017239:Paclitaxel; D002945:Cisplatin
keywords: Cervical squamous cell carcinomas; Paclitaxel; PinX1; Spindle assembly checkpoint; Telomere dysfunction