期刊
MOLECULAR ONCOLOGY
卷 9, 期 3, 页码 628-639出版社
WILEY
DOI: 10.1016/j.molonc.2014.10.014
关键词
Prostate cancer; Androgen signaling; Taxanes; Therapeutic resistance; Epithelial-mesenchymal transition
类别
资金
- National Institutes of Health, (NIDDK) [R01-00491815]
- James F. Hardymon Endowment
- National Cancer Institute [2R01 CA105304]
- Canadian Institutes of Health Research [MOP79308]
- US Army Medical Research and Materiel Command Prostate Cancer Research Program [W81XWH-11-1-0551]
Taxane-based chemotherapy is an effective treatment for castration-resistant-prostate cancer (CRPC) via stabilization of microtubules. Previous studies identified that the inhibitory effect of microtubule-targeting chemotherapy on androgen receptor (AR) activity was conferred by interfering with AR intracellular trafficking. The N-terminal domain (NTD) of AR was identified as a tubulin-interacting domain that can be effectively targeted by the novel small molecule inhibitor, EPI. Taken together this evidence provided the rationale that targeting AR nuclear translocation and activity via a combination of an antagonist of the AR NTD and taxane-based chemotherapy may enhance the therapeutic response in CRPC. The present study investigated the anti-tumor efficacy of a combination of EPI with Docetaxel chemotherapy, in cell models of CRPC, harboring the AR splice variants in addition to the full length AR. Our findings demonstrate that there was no significant effect on the androgen-mediated nuclear transport of AR variants and AR transcriptional activity by Docetaxel. The therapeutic response to Docetaxel was enhanced by inhibition of the NTD of AR (by EPI) through cycling of epithelial-mesenchymal-transition (EMT) to mesenchymal-epithelial-transition (MET) among prostate cancer epithelial cells. These results support that transient programming of EMT by the AR NTD inhibitor, potentially drives the sensitivity of prostate tumors with differential distribution of AR variants to microtubule-targeting chemotherapy. This study is of major significance in dissecting mechanisms to overcome taxane resistance in advanced CRPC. (c) 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
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