Significance and mechanism of androgen receptor... : Hepatology (original) (raw)

Original Articles: HEPATOBILIARY MALIGNANCIES

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

Zhang, Hong1,2,†; Li, Xiao‐Xing1,†; Yang, Yang1; Zhang, Yanjie*,3; Wang, Hui‐Yun*,1,2; Zheng, X.F. Steven*,1,2

1State Key Laboratory of Oncology in South China, and Collaborative Innovation Center for Cancer MedicineSun Yat‐Sen University Cancer CenterGuangzhouChina

2Rutgers Cancer Institute of New Jersey and Department of Pharmacology, Robert Wood Johnson Medical School, RutgersThe State University of New JerseyNew BrunswickNJ

3Oncology Department, Shanghai Ninth People's HospitalShanghai Jiaotong University School of MedicineShanghaiChina

* ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:
X.F. Steven Zheng, Ph.D.
Rutgers Cancer Institute of New Jersey and Department of Pharmacology, Robert Wood Johnson Medical School Rutgers, The State University of New Jersey
New Brunswick, NJ 08903
E‐mail: [email protected]
Tel: +1‐732‐235‐6879; or
Hui‐Yun Wang, M.D., Ph.D.
State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Sun Yat‐Sen University Cancer Center
651 Dongfeng East Road
Guangzhou 510060, China
E‐mail: [email protected]
Tel: +86‐20‐8734‐3308; or
Yanjie Zhang, M.D., Ph.D.
Oncology Department, Shanghai Ninth People's Hospital Shanghai Jiaotong University School of Medicine
Shanghai 201999, China
E‐mail: [email protected]
Tel: +86‐21‐56693614

†These authors contributed equally to this work.

Abstract

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).