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

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...

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Published in:Hepatology (Baltimore, Md.) Md.), 2018-06, Vol.67 (6), p.2271-2286
Main Authors: Zhang, Hong, Li, Xiao‐Xing, Yang, Yang, Zhang, Yanjie, Wang, Hui‐Yun, Zheng, X.F. Steven
Format: Article
Language:English
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
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Summary: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).
ISSN:0270-9139
1527-3350
DOI:10.1002/hep.29715