Secreted miR-210-3p, miR-183-5p and miR-96-5p reduce sensitivity to docetaxel in prostate cancer cells

• Published in: Cell death discovery Vol. 9; no. 1; p. 445
• Main Authors: Canovai, Maristella, Evangelista, Monica, Mercatanti, Alberto, D’Aurizio, Romina, Pitto, Letizia, Marrocolo, Francesca, Casieri, Valentina, Pellegrini, Marco, Lionetti, Vincenzo, Bracarda, Sergio, Rizzo, Milena
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.12.2023; Springer Nature B.V; Nature Publishing Group
• Subjects: 631/337/384/331; 631/67/1059/2326; 631/67/589/466; Apoptosis; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Cycle Analysis; Cell interactions; Cytotoxicity; Drug resistance; Exosomes; FOXO1 protein; Horizontal transfer; Insulin-like growth factor-binding protein 3; Life Sciences; Metastases; Phenotypes; Prostate cancer; Stem Cells
• ISSN: 2058-7716; 2058-7716
• DOI: 10.1038/s41420-023-01696-4

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 sDCT R -miRNAs) are specifically released by DCT resistant (DCT R ) PCa clones and decrease the efficacy of DCT in PCa cells when overexpressed. Through bioinformatic analysis, we identified several potential targets of sDCT R -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 sDCT R -miRNAs to reduce the efficacy of DCT. We explored whether secreted sDCT R -miRNAs could affect the phenotype of PCa cells. We found that exposure to exosomes derived from DCT R PCa clones (in which the content of sDCT R -miRNAs was higher than in exosomes from parental cells), as well as exposure to exosome loaded with sDCT R -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.