Abiraterone induces SLCO1B3 expression in prostate cancer via microRNA-579-3p

Abstract

Understanding mechanisms of resistance to abiraterone, one of the primary drugs approved for the treatment of castration resistant prostate cancer, remains a priority. The organic anion polypeptide 1B3 (OATP1B3, encoded by SLCO1B3) transporter has been shown to transport androgens into prostate cancer cells. In this study we observed and investigated the mechanism of induction of SLCO1B3 by abiraterone. Prostate cancer cells (22Rv1, LNCaP, and VCAP) were treated with anti-androgens and assessed for SLCO1B3 expression by qPCR analysis. Abiraterone treatment increased SLCO1B3 expression in 22Rv1 cells in vitro and in the 22Rv1 xenograft model in vivo. MicroRNA profiling of abiraterone-treated 22Rv1 cells was performed using a NanoString nCounter miRNA panel followed by miRNA target prediction. TargetScan and miRanda prediction tools identified hsa-miR-579-3p as binding to the 3′-untranslated region (3′UTR) of the SLCO1B3. Using dual luciferase reporter assays, we verified that hsa-miR-579-3p indeed binds to the SLCO1B3 3′UTR and significantly inhibited SLCO1B3 reporter activity. Treatment with abiraterone significantly downregulated hsa-miR-579-3p, indicating its potential role in upregulating SLCO1B3 expression. In this study, we demonstrated a novel miRNA-mediated mechanism of abiraterone-induced SLCO1B3 expression, a transporter that is also responsible for driving androgen deprivation therapy resistance. Understanding mechanisms of abiraterone resistance mediated via differential miRNA expression will assist in the identification of potential miRNA biomarkers of treatment resistance and the development of future therapeutics.

miR579-3p is an inhibitory modulator of neointimal hyperplasia and transcription factors c-MYB and KLF4

“…S2A) and interestingly, also predicted to target both KLF4 and c-MYB. There are only a very small number of reports related to miR579-3p, mainly involving cancer cells [41,[44][45][46]. Its function in SMCs and IH was not known.…”

A novel prognostic model based on three clinic-related miRNAs for prostate cancer

“…MiR-1246 was demonstrated to promote the progression of hepatocellular carcinoma through activating the RORα-Wnt/β-Catenin axis ( 16 ). Barbier et al revealed that miR-579-3p participates in the abiraterone-induced SLCO1B3 expression in PCa and further elucidated the mechanisms of abiraterone resistance ( 17 ). Byun et al identified that the urinary microRNA-1913 to microRNA-3659 expression ratio is potentially a noninvasive diagnostic biomarker for PCa ( 18 ).…”

MicroRNAs in the Regulation of Solute Carrier Proteins Behind Xenobiotic and Nutrient Transport in Cells

“…Dysregulation of both miRNA and solute carrier transporters have been shown to be associated with chemoresistance ( Si et al, 2019 ; Sun et al, 2020 ; Rashid et al, 2021 ). MiR-579-3p was found to directly downregulate SLCO1B3 in pancreatic cancer cells, whereas the androgen biosynthesis inhibitor abiraterone downregulates miR-579-3p ( Barbier et al, 2021 ) ( Table 4 ). SLCO1B3 is also involved in the influx of testosterone, so the increase in SLCO1B3 is associated with resistance to androgen deprivation therapy ( Barbier et al, 2021 ).…”

“…MiR-579-3p was found to directly downregulate SLCO1B3 in pancreatic cancer cells, whereas the androgen biosynthesis inhibitor abiraterone downregulates miR-579-3p ( Barbier et al, 2021 ) ( Table 4 ). SLCO1B3 is also involved in the influx of testosterone, so the increase in SLCO1B3 is associated with resistance to androgen deprivation therapy ( Barbier et al, 2021 ). In acute lymphoblastic leukemia, miR-595 downregulates the methotrexate transporter SLC19A1 with rs1051296 G > T polymorphism, and this decrease in SLC19A1 causes reduced methotrexate influx and sensitivity ( Wang et al, 2018 ).…”