Interference with the androgen receptor protein stability in therapy‐resistant prostate cancer

Abstract

The androgen receptor (AR) plays a central role in the pathogenesis of prostate cancer (PCa). Most PCa cases develop eventually from an androgen-dependent stage to castration-resistant prostate cancer (CRPC) with AR-signaling still being active. Thus, inhibition of AR remains a well-established promising drug target in CRPC. However, despite the improvements of current treatment for CRPC by targeting the AR, the evolution of adaptive AR-signaling leads to therapy-resistant CRPC. Treatment failure is based mostly on the inability to keep AR under long-term restraint due to adaptive responses of AR-signaling. One underlying mechanism appears to be the increased AR protein stability. Therefore, the regulation of AR protein stability and its degradation is another interesting path that could enhance our knowledge of carcinogenesis and tumor evolution possibly leading to novel therapeutic targets. In this review, we discuss various molecular mechanisms and factors that stabilize AR protein levels directly or indirectly. We summarize novel approaches to interfere with AR stability including targeting the glucocorticoid receptor (GR), heat shock proteins, and co-chaperones as well as E3-ligases using small chimeric molecules. These novel approaches in combination with antiandrogen treatment inhibit PCa growth through the regulation of AR protein levels.

RNA‐binding protein Musashi2 stabilizing androgen receptor drives prostate cancer progression

“…After stimulation with DHT for 24 h, stable cell lines were treated with CHX for 0, 1 h, 3 h, 6 h, 12 h or 24 h, and the CHX time‐gradient experiments suggested that AR was rapidly degraded in shMSI2 cells compared with that of shCon cells (Figure C). Most proteins are degraded in the following three ways: autophagy, lysosomal‐mediated and proteasomal‐mediated degradation . Contrary to autophagy inhibitors 3‐methyladenine (3‐MA) and lysosome function inhibitor chloroquine, only the proteasome inhibitor MG132 could rescue the AR protein level in C4‐2B shMSI2‐1 stable lines (Figure A‐C).…”

“…Our CHX time‐course experiments showed that AR protein stability was decreased in shMSI2 cells compared with that in shCon cells, indicating a translational regulatory function for AR protein stability of MSI2. The AR protein degradation level is controlled by various pathways, including proteasome, autophagy and lysosome systems . While 3‐MA and chloroquine could not rescue the AR downregulation caused by MSI2 knockdown, the MG132 inhibitory experiment focused our interest on proteasome‐mediated degradation.…”

Mechanisms of Androgen Receptor Agonist- and Antagonist-Mediated Cellular Senescence in Prostate Cancer

“…The AR is a nuclear hormone receptor and a ligand-controlled transcription factor belonging to the nuclear receptor superfamily. In the absence of ligand, the AR is primarily localized in the cytoplasm bound in a complex with multiple chaperones (heat shock proteins), which incapacitate AR from entering to the nucleus [11,12]. Upon androgen binding, AR forms a homodimer, changes its conformation including an interaction between the AR amino (N)-terminal FXXLF motif and the carboxyl (C)-terminal AF-2 domain containing the LXXLL motif and dissociation from the heat shock proteins leading to nuclear translocation [13,14].…”

Senolytic compounds control a distinct fate of androgen receptor agonist- and antagonist-induced cellular senescent LNCaP prostate cancer cells

“…Therefore, androgen deprivation therapy and inhibition of the ARsignaling by AR antagonists are the major forms of PCa hormone therapy. However, after a period of time, the cancer becomes resistant through adaptive responses of AR-signaling and activation of other signaling mechanisms [4][5][6]. Interestingly, supraphysiological androgen levels (SAL) are used in clinical trials so-called bipolar androgen therapy (BAT) as another approach to AR antagonists [7,8].…”