title: Induction of paclitaxel resistance by ERα mediated prohibitin mitochondrial-nuclear shuttling.
abstract: Paclitaxel is a drug within one of the most promising classes of anticancer agents. Unfortunately, clinical success of this drug has been limited by the insurgence of cellular resistance. To address this, Paclitaxel resistance was modeled in an in vitro system using estrogen treated prostate cancer cells. This study demonstrates that emerging resistance to clinically relevant doses of Paclitaxel is associated with 17-β-estradiol (E2) treatment in PC-3 cells, but not in LNCaP cells. We found that small interfering RNA mediated knockdown of ERα lead to a decrease in E2 induced Paclitaxel resistance in androgen-independent cells. We also showed that ERα mediated the effects of estrogen, thereby suppressing androgen-independent cell proliferation and mediating Paclitaxel resistance. Furthermore, E2 promoted Prohibitin (PHB) mitochondrial-nucleus translocation via directly mediation of ERα, leading to an inhibition of cellular proliferation by PHB. Additionally, restoration of Paclitaxel sensitivity by ERα knockdown could be overcome by PHB overexpression and, conversely, PHB knockdown decreased E2 induced Paclitaxel resistance. These findings demonstrate that PHB lies downstream of ERα and mediates estrogen-dependent Paclitaxel resistance signaling cascades.
authors.affiliation: State Key Laboratory of Oncology in South China, Department of Urology, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China ; Guangdong Key Laboratory of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
authors.forename: Pei
authors.initials: P
authors.lastname: Dong
authors.affiliation: State Key Laboratory of Oncology in South China, Department of Urology, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Oncology in South China, Department of Urology, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China.
authors.forename: Jianye
authors.initials: J
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Oncology in South China, Department of Urology, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China.
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Oncology in South China, Department of Urology, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China.
authors.forename: Shengjie
authors.initials: S
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Oncology in South China, Department of Urology, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China.
authors.forename: Ziling
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Oncology in South China, Department of Urology, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China.
authors.forename: Fangjian
authors.initials: F
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Oncology in South China, Department of Urology, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China.
authors.forename: Zhuowei
authors.initials: Z
authors.lastname: Liu
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology*; D000091402:Prohibitins; D011471:Prostatic Neoplasms / Q000473:pathology; D012097:Repressor Proteins / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; C000717328:PHB protein, human; D000091402:Prohibitins; D012097:Repressor Proteins; D017239:Paclitaxel