Recent studies support the role of steroid hormone transporters in modulating intratumoral androgen concentrations, thereby promoting castration-resistant prostate cancer (CRPC) progression. The organic anion polypeptide 1B3 (OATP1B3) transporter is expressed de novo in prostate tumors and contributes to the transport of androgen into these cells. Polymorphic variations in the SLCO1B3 gene encoding OATP1B3 are related to clinical outcome in men with prostate cancer receiving androgen deprivation therapy (ADT) or those with CRPC. The current study elucidates the mechanism of de novo SLCO1B3 expression in prostate cancer. We discovered that chetomin, a known inhibitor of HIF-1α- and CBP/p300 binding, was a potent inducer of SLCO1B3 transcripts.
We investigated the transcriptional regulation of SLCO1B3 expression by CBP/p300 using siRNA-mediated gene silencing or treatment with various CBP/p300 inhibitors (C646, HATi II) to determine the effects on gene transcription, downstream pathways, and transporter-dependent uptake studies.
Treatment with various CBP/p300 inhibitors (CH1 or HAT binding domains) significantly increased the expression of SLCO1B3 and subsequent transporter-mediated androgen uptake in tumor cells. Specific downregulation of p300 or CBP by siRNA reduced SLCO1B3 expression in prostate cancer cells (22Rv1, LNCaP, and PC3), suggesting that CBP/p300 interacts with specific transcription factors essential for driving SLCO1B3 expression. Cells treated with ADT elicited differential effects on transporter expression in AR-positive vs AR-null cells. Studies are currently underway to identify cofactors involved in forming the CBP/p300 transcriptional complex regulating SLCO1B3 expression.
De novo OATP1B3 expression in prostate cancer is a mechanism of tumoral resistance to ADT resulting in greater androgen uptake. Taken together, the data suggest that ADT resistance and transporter-dependent increased uptake of residual androgens result from CBP/p300-mediated SLCO1B3 expression. OATP1B3 should be considered a viable biological target for therapeutic intervention in prostate cancer.
Clinical trial identification
Legal entity responsible for the study
National Institutes of Health
National Cancer Institute (NIH)
All authors have declared no conflicts of interest.