Dual androgen receptor (AR) and STAT3 inhibition by a compound targeting the AR amino‐terminal domain

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.

Current and emerging approaches to noncompetitive AR inhibition

“…112 Studies have shown that cinobufagin-3-acetate binds directly to the NTD thus inhibiting AR-STAT3 signaling-a pathway that is a key driver in the progression to CRPC. 113 The compound demonstrated static levels of AR inhibition in the presence of varying concentrations of R1881, discounting a mechanism that functions via the LBP. Cinobufagin-3-acetate displayed significant inhibition against the clinical variants AR-V7 and ARv567es in LNCaP cells at concentrations of 1 and 10 µM, respectively, and was found to reduce AR protein expression without altering AR mRNA levels or reducing AR nuclear translocation.…”

“…Cinobufagin‐3‐acetate is a steroidal natural product secreted by the asiatic toad, Bufo gargarizans (Figure 16B). 112 Studies have shown that cinobufagin‐3‐acetate binds directly to the NTD thus inhibiting AR‐STAT3 signaling—a pathway that is a key driver in the progression to CRPC 113 . The compound demonstrated static levels of AR inhibition in the presence of varying concentrations of R1881, discounting a mechanism that functions via the LBP.…”

Androgen Receptor-Dependent Mechanisms Mediating Drug Resistance in Prostate Cancer

“…Subsequently, STAT3 activity increases AR recruitment to AR target genes such as to the PSA promoter. It is suggested that STAT3 pathway is essential to drive PCa progression to mCRPC by in part by reactivating the AR pathway [ 136 , 137 ]. In addition, STAT3 activation may promote Enz resistance of CRPC.…”

“…In addition, STAT3 activation may promote Enz resistance of CRPC. Because of that, inhibition of STAT3 has been an interesting treatment for potential therapy [ 137 , 138 , 139 ]. It was reported that inhibition of STAT3 results in decreased growth of Enz-resistant cells.…”