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Generation of Prostate Cancer Cell Models of Resistance to the Anti-mitotic Agent Docetaxel
Published on: September 8, 2017
Secreted miR-210-3p, miR-183-5p and miR-96-5p reduce sensitivity to docetaxel in prostate cancer cells
Maristella Canovai1, Monica Evangelista1, Alberto Mercatanti1
1Institute of Clinical Physiology (IFC), CNR, Pisa, Italy.
Abstract:
Docetaxel (DCT) resistance is one of the main factors responsible for treatment failure in metastatic prostate cancer (PCa). Although several mechanisms of DCT resistance have been elucidated, the issue is still far from comprehensive. In this work we show that miR-96-5p, miR-183-5p and miR-210-3p (referred to as sDCTR-miRNAs) are specifically released by DCT resistant (DCTR) PCa clones and decrease the efficacy of DCT in PCa cells when overexpressed. Through bioinformatic analysis, we identified several potential targets of sDCTR-miRNAs' activity including FOXO1, IGFBP3, and PDCD4 known to exert a role in DCT resistance. Additionally, we found that PPP2CB and INSIG1 mediated the ability of sDCTR-miRNAs to reduce the efficacy of DCT. We explored whether secreted sDCTR-miRNAs could affect the phenotype of PCa cells. We found that exposure to exosomes derived from DCTR PCa clones (in which the content of sDCTR-miRNAs was higher than in exosomes from parental cells), as well as exposure to exosome loaded with sDCTR-miRNAs, reduced the cytotoxicity of DCT in PCa cells sensitive to the drug. Finally, we validated circulating miR-183-5p and miR-21-5p as potential predictive biomarkers of DCT resistance in PCa patients. Our study suggests a horizontal transfer mechanism mediated by exosomal miRNAs that contributes to reduce docetaxel sensitivity and highlights the relevance of cell-to-cell communication in drug resistance.
Insights
Specific miRNAs released by docetaxel-resistant prostate cancer cells reduce drug efficacy. Circulating miR-183-5p and miR-21-5p may predict resistance, suggesting exosomal miRNA transfer impacts treatment outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Docetaxel resistance is a major challenge in metastatic prostate cancer (PCa) treatment.
- Existing knowledge on docetaxel resistance mechanisms remains incomplete.
- Understanding novel resistance pathways is crucial for improving PCa therapy.
Purpose of the Study:
- To investigate the role of specific secreted miRNAs in docetaxel resistance in PCa.
- To identify potential biomarkers for predicting docetaxel resistance in PCa patients.
- To elucidate the mechanism of exosomal miRNA-mediated drug resistance.
Main Methods:
- Identification and characterization of specific miRNAs (miR-96-5p, miR-183-5p, miR-210-3p) released by docetaxel-resistant PCa cells.
- Bioinformatic analysis to predict targets of these miRNAs.
- Experimental validation of miRNA effects on docetaxel efficacy using PCa cell lines.
- Investigation of exosome-mediated transfer of miRNAs and their impact on docetaxel sensitivity.
- Validation of circulating miRNAs as potential biomarkers in PCa patients.
Main Results:
- Three specific miRNAs (miR-96-5p, miR-183-5p, miR-210-3p) were identified as secreted by docetaxel-resistant PCa cells and decrease docetaxel efficacy.
- Potential targets including FOXO1, IGFBP3, PDCD4, PPP2CB, and INSIG1 were identified.
- Exosomes from resistant cells, or loaded with these miRNAs, reduced docetaxel cytotoxicity in sensitive PCa cells.
- Circulating miR-183-5p and miR-21-5p were validated as potential predictive biomarkers for docetaxel resistance.
Conclusions:
- Secreted exosomal miRNAs mediate horizontal transfer, contributing to docetaxel resistance in PCa.
- Cell-to-cell communication via exosomal miRNAs is a significant factor in overcoming docetaxel sensitivity.
- Circulating miR-183-5p and miR-21-5p show promise as predictive biomarkers for docetaxel resistance in prostate cancer patients.
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