Regression Of Castration-Resistance Prostate Cancer By A Natural Compound Ailanthone And Its Molecular Mechanisms

Prostate cancer (PCa) is the most common male malignancy in many industrialized countries. PCa depends on androgenic signaling for growth and survival. Androgen ablation therapy causes a temporary reduction in prostate cancer tumor burden, but it will grow again in the absence of androgens to form castration-resistant prostate cancer (CRPC). The emerging mechanisms of CRPC progression include AR amplification and overexpression, AR gene rearrangement, and promoting synthesis of constitutively active truncated AR splice variants (AR-Vs) that lack the AR ligand-binding domain. Recently clinical researches reported and confirmed that targeting of the AR is a valid therapeutic strategy in CRPC. Indeed, recent clinical trials have shown that a new generation anti-androgen enzalutamide (MDV3100) or novel inhibitor targeting androgen synthesis abiraterone acetate are effective for CRPC. However, many studies recently reported that constitutively active posttranslational splice variants of the AR which lacking of ligand binding domain (LBD) are resistant to the anti-androgen therapy. Collectively, both ligand-dependent full-length androgen receptor and its splice variants mediate distinct transcriptional programs in castration-resistant prostate cancerIn this study, aiming to block both full-length and constitutively active truncated AR, we used the MMTV-luciferase reporter system which contains the androgen response elements (AREs) to screen the natural compound library in our lab. Herein, we identified a natural small-molecule ailanthone (AIL) which potently blocked the transcriptional activities of both DHT-induced full-length AR and constitutively-active AR1-651 which is lacking of LBD. Moreover, AIL effectively down-regulated AR protein level and its target genes both in the prostate cell lines and 22RV1 orthotopic xenograft of castrated nude mice. Notably, AIL reduced not only the full length androgen receptor (AR-FL) but also the constitutively active truncated AR splice variants (AR-Vs) in protein level. We also demonstrated that AIL disrupted the interaction between AR and the chaperones Hsp90, Hsp70 and Hsp40. Especially, AIL prevented the interaction between Hsp90 and p23 through binding p23, by which disruption of the AR-chaperones complex and then AR was ubiquitinated and degradated through proteasome-mediated pathway. In animal model, administration of 2 mg/kg AIL effectively suppressed the growth of MDV3100 as well as bicalutamide resistant 22RV1 cells both in intact and castrated male mice, In addition, we found that the activities of main CYP enzymes were not effected by AIL in vitro. These findings suggest that AIL is a promising small molecule to develop therapeutics for CRPC.