Significance and mechanism of androgen receptor overexpression and androgen receptor/mechanistic target of rapamycin cross‐talk in hepatocellular carcinoma

• Published in: Hepatology (Baltimore, Md.) Vol. 67; no. 6; pp. 2271 - 2286
• Main Authors: Zhang, Hong, Li, Xiao‐Xing, Yang, Yang, Zhang, Yanjie, Wang, Hui‐Yun, Zheng, X.F. Steven
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.06.2018
• Subjects: AKT protein; Androgen receptors; Androgens; Animals; Apoptosis; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - genetics; Cell Nucleus; Cell survival; Clinical trials; Feedback; Gene expression; Gene Expression Regulation, Neoplastic; Hepatocellular carcinoma; Hepatology; Humans; Liver cancer; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Localization; Medical prognosis; Mice; Nuclei; Phenylthiohydantoin - analogs & derivatives; Phenylthiohydantoin - therapeutic use; Rapamycin; Receptor Cross-Talk; Receptors, Androgen - biosynthesis; Receptors, Androgen - genetics; Receptors, Androgen - physiology; TOR protein; TOR Serine-Threonine Kinases - physiology; Tumor Cells, Cultured; Tumors; Ubiquitin
• ISSN: 0270-9139; 1527-3350
• DOI: 10.1002/hep.29715

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 antiandrogen and anti‐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% of 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 (mechanistic target of rapamycin) 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, cotargeting 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 attributed to feedback activation of the AKT‐mTOR pathway. Moreover, mTOR drives nuclear AR overexpression. Cotargeting AR and mTOR is a promising therapeutic strategy for HCC. (Hepatology 2018;67:2271‐2286).