Abstract
Prostate cancer (PCa) often recurs as incurable castration-resistant prostate cancer (CRPC) after the failure of androgen deprivation therapy. CRPC development relies on androgen receptor (AR) signaling. The IL6/STAT3 pathway is also a key driver of CRPC. The crosstalk between IL6/STAT3 and the AR pathways provides opportunities to explore next-generation agents to treat PCa. Through screening of around 600 natural compounds in our newly established prostate tumorigenesis model, potential STAT3 signaling inhibitors were found and additionally examined for effects on AR signaling. The small molecular compound 154 exhibited dual effects on IL6/STAT3 and AR pathways. We show here that compound 154 inhibits AR and STAT3 transcriptional activity, reduces the expression of phosphorylation of STAT3 (Y705) and downregulates the mRNA levels of AR target genes. Compound 154 also inhibits protein expression of AR and AR splice variants (ARv567es and AR-V7) without altering AR mRNA levels. Compound 154 binds to AR directly, but not to STAT3 and is identified as an antagonist of the AR amino-terminal domain (NTD) by disrupting protein-protein interactions between STAT3 and the AR NTD. Moreover, compound 154 does not reduce AR nuclear translocation. Compound 154 possesses the potential to become a leading compound in novel therapies against CRPC.