Significance and Mechanism of Androgen Receptor (AR) Overexpression and AR-mTOR Crosstalk in Hepatocellular Carcinoma

摘要

Hepatocellular carcinoma (HCC) is a male-dominant cancer and androgen receptor (AR) has been linked to the pathogenesis of HCC. However, AR expression and its precise role in HCC remain controversial. Moreover, previous anti-androgen and -AR clinical trials in HCC failed to demonstrate clinical benefits. In this study, we found that AR is overexpressed in the nucleus of approximately 37% HCC tumors, which is significantly associated with advanced disease stage and poor survival. AR overexpression in HCC cells markedly alters AR-dependent transcriptome, stimulates oncogenic growth and determines therapeutic response to enzalutamide, a second generation of AR antagonist. However, AR inhibition evokes feedback activation of AKT-mTOR signaling, a central regulator for cell growth and survival. On the other hand, mTOR promotes nuclear AR protein expression by restraining ubiquitin-dependent AR degradation and enhancing AR nuclear localization, providing a mechanistic explanation for nuclear AR overexpression in HCC. Finally, co-targeting AR and mTOR shows significant synergistic anti-HCC activity and decreases tumor burden by inducing apoptosis in vivo. Conclusion: Nuclear AR overexpression is associated with the progression and prognosis of HCC. However, enzalutamide alone has limited therapeutic utility due to feedback activation of AKT-mTOR pathway. Moreover, mTOR drives nuclear AR overexpression. Co-targeting AR and mTOR is a promising therapeutic strategy for HCC.