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Updated: Dec 6, 2025

Generation of Prostate Cancer Cell Models of Resistance to the Anti-mitotic Agent Docetaxel
Published on: September 8, 2017
Increased ABCC4 Expression Induced by ERRα Leads to Docetaxel Resistance via Efflux of Docetaxel in Prostate Cancer
Houbao Huang1, Jing Li2, Jing Shen3,4
1Department of Urology, Yijishan Affiliated Hospital, Wannan Medical College, Wuhu, China.
Abstract:
Docetaxel is a major treatment for advanced prostate cancer (PCa); however, its resistance compromises clinical effectiveness. Estrogen receptor-related receptor alpha (ERRα) belongs to an orphan nuclear receptor superfamily and was recently found to be closely involved in cancer. In the present study, we found that ERRα was involved in docetaxel resistance in PCa. Overexpression of ERRα conferred docetaxel resistance in PCa cell lines, and cells with ERRα downregulation were more sensitive to docetaxel. Among the drug resistance-related genes, ABCC4 demonstrated synchronous expression after ERRα manipulation in cells. Moreover, both ERRα and ABCC4 were overexpressed in the docetaxel-resistant cell, which could be reversed by ERRα knockdown. The knockdown of ERRα also reversed the reduced drug accumulation in the docetaxel-resistant cell. We also demonstrated for the first time that ABCC4 was a direct target of ERRα as determined by the CHIP and luciferase assays. Bioinformatics analysis revealed high expression of ERRα and ABCC4 in PCa patients, and a number of potential ERRα/ABCC4 targets were predicted. In conclusion, our study demonstrated a critical role for ERRα in docetaxel resistance by directly targeting ABCC4 and stressed the importance of ERRα as a potential therapeutic target for drug-resistant PCa.
Insights
Estrogen receptor-related receptor alpha (ERRα) drives docetaxel resistance in prostate cancer (PCa) by targeting ABCC4. Targeting ERRα may overcome drug resistance in PCa patients.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Docetaxel is a primary treatment for advanced prostate cancer (PCa).
- Docetaxel resistance significantly limits its clinical efficacy.
- Estrogen receptor-related receptor alpha (ERRα) is implicated in various cancers.
Purpose of the Study:
- To investigate the role of ERRα in docetaxel resistance in PCa.
- To identify molecular mechanisms linking ERRα to docetaxel resistance.
- To evaluate ERRα as a potential therapeutic target for drug-resistant PCa.
Main Methods:
- Prostate cancer cell line experiments involving ERRα overexpression and knockdown.
- Gene expression analysis of ERRα and ABCC4.
- Chromatin immunoprecipitation (CHIP) and luciferase assays to determine gene targeting.
- Bioinformatics analysis of ERRα and ABCC4 expression in PCa patients.
Main Results:
- ERRα overexpression conferred docetaxel resistance, while its downregulation increased sensitivity.
- ABCC4 expression was synchronously regulated by ERRα.
- ERRα directly targets ABCC4, leading to its overexpression in resistant cells.
- ERRα knockdown reversed docetaxel resistance and restored drug accumulation.
Conclusions:
- ERRα plays a critical role in mediating docetaxel resistance in prostate cancer.
- ERRα directly targets ABCC4, contributing to drug resistance.
- ERRα represents a promising therapeutic target for overcoming docetaxel resistance in PCa.
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