Abstract
Docetaxel and cabazitaxel are taxane chemotherapy treatments for metastatic castration-resistant prostate cancer (CRPC). However, therapeutic resistance remains a major issue. MicroRNAs are short non-coding RNAs that can silence multiple genes, regulating several signalling pathways simultaneously. Therefore, synthetic microRNAs may have therapeutic potential in CRPC by regulating genes involved in taxane response and minimise compensatory mechanisms that cause taxane resistance. To identify microRNAs that can improve the efficacy of taxanes in CRPC, we performed a genome-wide screen of 1280 microRNAs in the CRPC cell lines PC3 and DU145 in combination with docetaxel or cabazitaxel treatment. Mimics of miR-217 and miR-181b-5p enhanced apoptosis significantly in PC3 cells in the presence of these taxanes. These mimics downregulated at least a thousand different transcripts, which were enriched for genes with cell proliferation and focal adhesion functions. Individual knockdown of a selection of 46 genes representing these transcripts resulted in toxic or taxane sensitisation effects, indicating that these genes may be mediating the effects of the microRNA mimics. A range of these genes are expressed in CRPC metastases, suggesting that these microRNA mimics may be functional in CRPC. With further development, these microRNA mimics may have therapeutic potential to improve taxane response in CRPC patients.
Highlights
Prostate cancer is the second most frequently diagnosed cancer in men worldwide, and the third leading cause of male cancer death in developed countries[1]
The cells in the screen were treated with sub-optimal doses of docetaxel and cabazitaxel equivalent to an IC20 dose. Given that these doses of taxanes decreased cell viability by 20% in non-targeting control cells, we considered a microRNA mimic or inhibitor as a taxane sensitiser if it decreased cell viability by more than 20% with taxane treatment – i.e. viability of taxane-treated cells transfected with mimic or inhibitor is 80% of the viability of vehicle-treated cells transfected with non-targeting control
The expression profile of these genes vary with metastatic site and disease stage, the ability of microRNAs to affect multiple targets and the presence of more than one gene target in castration-resistant prostate cancer (CRPC) indicates that these microRNA mimics may be effective in a range of CRPC metastases
Summary
Prostate cancer is the second most frequently diagnosed cancer in men worldwide, and the third leading cause of male cancer death in developed countries[1]. Despite the rise in new therapeutics for metastatic castration-resistant prostate cancer (CRPC) such as novel anti-androgens, radium-223 and PARP inhibitors[2,3], the taxanes docetaxel and cabazitaxel are the standard of care chemotherapy treatments for CRPC. The availability of large libraries of microRNA mimics or inhibitors enables the use of genome-wide screens to identify microRNAs that can increase the sensitivity of cancer cells to a drug. This approach was commonly used with small-interfering RNA (siRNA) libraries to identify synthetic lethal genes[17] but has been demonstrated with microRNA libraries. Lam et al identified 19 microRNAs that sensitised colorectal cancer cells to a BCL2 inhibitor from a screen of 810 microRNA mimics combined with the drug[18]
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