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

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.

miRNAs: From Master Regulators of Gene Expression to Biomarkers Involved in Intercellular Communication

“…Another aspect of ex-miRNAs, which is still debated, is their role in intercellular communication, either as free molecules or as encapsulated vesicles (such as exosomes or other types of extracellular vesicles). There are many indications that ex-miRNAs can act as signaling molecules in both an autocrine/paracrine and an endocrine manner, influencing physiological and pathological processes (e.g., [11][12][13]), including drug resistance (e.g., [14]). Zeng et al [15] reviewed some examples of exosomal miRNAs that play a role in cell-cell communication in pathological states, highlighting their therapeutic potential.…”