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Updated: Mar 2, 2026

Generation of Prostate Cancer Cell Models of Resistance to the Anti-mitotic Agent Docetaxel
Published on: September 8, 2017
MicroRNA-181a promotes docetaxel resistance in prostate cancer cells
Cameron M Armstrong1, Chengfei Liu1, Wei Lou1
1Department of Urology, University of California Davis, Sacramento, California.
Background:
Docetaxel is one of the primary drugs used for treating castration resistant prostate cancer (CRPC). Unfortunately, over time patients invariably develop resistance to docetaxel therapy and their disease will continue to progress. The mechanisms by which resistance develops are still incompletely understood. This study seeks to determine the involvement of miRNAs, specifically miR-181a, in docetaxel resistance in CRPC.
Methods:
Real-time PCR was used to measure miR-181a expression in parental and docetaxel resistant C4-2B and DU145 cells (TaxR and DU145-DTXR). miR-181a expression was modulated in parental or docetaxel resistant cells by transfecting them with miR-181a mimics or antisense, respectively. Following transfection, cell number was determined after 48 h with or without docetaxel. Cross resistance to cabazitaxel induced by miR-181a was also determined. Western blots were used to determine ABCB1 protein expression and rhodamine assays used to assess activity. Phospho-p53 expression was assessed by Western blot and apoptosis was measured by ELISA in C4-2B TaxR and PC3 cells with inhibited or overexpressed miR-181a expression with or without docetaxel.
Results:
miR-181a is significantly overexpressed in TaxR and DU145-DTXR cells compared to parental cells. Overexpression of miR-181a in parental cells confers docetaxel and cabazitaxel resistance and knockdown of miR-181a in TaxR cells re-sensitizes them to treatment with both docetaxel and cabazitaxel. miR-181a was not observed to impact ABCB1 expression or activity, a protein which was previously demonstrated to be highly involved in docetaxel resistance. Knockdown of miR-181a in TaxR cells induced phospho-p53 expression. Furthermore, miR-181a knockdown alone induced apoptosis in TaxR cells which could be further enhanced by the addition of DTX.
Conclusions:
Overexpression of mir-181a in prostate cancer cells contributes to their resistance to docetaxel and cabazitaxel and inhibition of mir-181a expression can restore treatment response. This is due, in part, to modulation of p53 phosphorylation and apoptosis.
Insights
MicroRNAs, specifically miR-181a, drive resistance to docetaxel and cabazitaxel in castration resistant prostate cancer (CRPC). Inhibiting miR-181a restores treatment sensitivity by affecting p53 phosphorylation and apoptosis.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Docetaxel is a primary treatment for castration-resistant prostate cancer (CRPC).
- Acquired resistance to docetaxel limits its long-term efficacy in CRPC patients.
- Mechanisms of docetaxel resistance, including the role of microRNAs, are not fully understood.
Purpose of the Study:
- To investigate the role of miR-181a in the development of docetaxel resistance in CRPC.
- To determine if modulating miR-181a levels can overcome docetaxel resistance.
Main Methods:
- Quantitative real-time PCR to measure miR-181a expression in docetaxel-resistant prostate cancer cells.
- Transfection with miR-181a mimics or antisense oligonucleotides to modulate expression.
- Cell viability assays, Western blotting for ABCB1 and phospho-p53, and apoptosis assays (ELISA).
Main Results:
- miR-181a was significantly overexpressed in docetaxel-resistant cells.
- Overexpressing miR-181a induced resistance to docetaxel and cabazitaxel.
- Knockdown of miR-181a restored sensitivity to both drugs and induced apoptosis via p53 phosphorylation.
- miR-181a did not affect ABCB1 expression or activity.
Conclusions:
- miR-181a overexpression is a key factor in CRPC resistance to docetaxel and cabazitaxel.
- Inhibiting miR-181a can re-sensitize CRPC cells to chemotherapy.
- The mechanism involves the modulation of p53 phosphorylation and apoptosis.
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