Bruceantin targets HSP90 to overcome resistance to hormone therapy in castration-resistant prostate cancer

Abstract

Rationale: Aberrant androgen receptor (AR) signaling via full-length AR (AR-FL) and constitutively active AR variant 7 (AR-V7) plays a key role in the development of castration-resistant prostate cancer (CRPC) and resistance to hormone therapies. Simultaneous targeting of AR-FL and AR-V7 may be a promising strategy to overcome resistance to hormone therapy. This study aimed to identify novel drug candidates co-targeting AR-FL and AR-V7 activities and elucidate their molecular mechanism of anti-CRPC activities. Methods: Using a CRPC cell-based reporter assay system, we screened a small library of antimalarial agents to explore the possibility of repositioning them for CRPC treatment and identified bruceantin (BCT) as a potent anti-CRPC drug candidate. A series of cell-based, molecular, biochemical, and in vivo approaches were performed to evaluate the therapeutic potential and molecular mechanism of BCT in CRPC. These approaches include reporter gene assays, cell proliferation, RNA-seq, qRT-PCR, mouse xenografts, co-immunoprecipitation, GST pull-down, immobilized BCT pull-down, molecular modeling, and bioinformatic analyses. Results: We identified BCT as a highly potent inhibitor co-targeting AR-FL and AR-V7 activity. BCT inhibits the transcriptional activity of AR-FL/AR-V7 and downregulates their target genes in CRPC cells. In addition, BCT efficiently suppresses tumor growth and metastasis of CRPC cells. Mechanistically, BCT disrupts the interaction of HSP90 with AR-FL/AR-V7 by directly binding to HSP90 and inhibits HSP90 chaperone function, leading to degradation of AR-FL/AR-V7 through the ubiquitin-proteasome system. Clinically, HSP90 expression is upregulated and correlated with AR/AR-V7 levels in CRPC. Conclusion: Our findings suggest that BCT could serve as a promising therapeutic candidate against CRPC and highlight the potential benefit of targeting AR-FL/AR-V7-HSP90 axis to overcome resistance caused by aberrant AR-FL/AR-V7 signaling.

Medicinal Activities and Nanomedicine Delivery Strategies for Brucea javanica Oil and Its Molecular Components

“…In addition, BD has been found to inhibit hepatocellular carcinoma by inhibiting signaling pathways related to liver carcinogenesis and disease progression [ 35 ]. Quassinoids are typically more potent than fatty acids, with 50% inhibitory concentration (IC 50 ) values down to the nanomolar level [ 37 ], and hence most therapeutic focus has been on quassinoids [ 38 , 39 ].…”

A SIX1 degradation inducer blocks excessive proliferation of prostate cancer

“…Unfortunately, the regulatory mechanisms underlie CRPC development remains elusive. Various studies have been demonstrated that reactivation of AR that resulted from the genetic mutation and amplification, increased stability, and expressions of splice variants, may be the major mechanism that contributes to the progress from the androgen-dependent PC to CRPC 4 , 26 , 33 - 35 . Our previous study demonstrated a novel mechanism that SIX1 signal can also contribute to the progression of CRPC 20 .…”

Targeting Heat-Shock Protein 90 in Cancer: An Update on Combination Therapy

“…Hsp90 inhibitors also act synergistically with many other anticancer therapies, including photodynamic therapy (PDT) [ 117 ] and hormone therapy [ 118 , 119 , 120 ], via different mechanisms. Furthermore, some bifunctional drugs, such as STA-8666 (HSP90 inhibitor and topoisomerase inhibitor SN-38) [ 121 ], DHP1808 (HSP90-PI3K) [ 122 ] and MPT0G449, are essentially in combination.…”