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.