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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.
Highlights
Prostate cancer is one of the leading causes of death among men in developed countries
The mechanisms underlying the hormonal induction of prostate cancer in vivo remain uncertain, there is evidence to support that long term administration of androgens and estrogens results in an estrogenic environment in rat prostates and the ensuing development of cancer [20]
To examine whether estrogen is sufficient to regulate the progress of prostate cancer, we first examined the sensitivity of LNCaP cells and PC3 cells for Paclitaxel
Summary
Prostate cancer is one of the leading causes of death among men in developed countries. The primary treatment for hormonerefractory prostate cancer is taxane-based chemotherapy, including Paclitaxel [1]. Taxane-based therapy often improves patient survival, the cancer develops drug resistance in most patients, leading to recurrence of the cancer, distant metastasis and death [3]. Significant ERa gene expression as measured by mRNA and protein levels was observed in hormone refractory tumors and metastatic lesions, including lymph node and bone metastases [8]. These studies suggest that estrogen can affect prostatic cancerogenesis and neoplastic progression through an ER-mediated process in human prostate tissue. The mechanisms underlying estrogen and estrogen receptor signaling in human prostate tissue remain poorly understood
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