GRK3 is a direct target of CREB activation and regulates neuroendocrine differentiation of prostate cancer cells

// Meixiang Sang 1, 7, * , Mohit Hulsurkar 1, 5, * , Xiaochong Zhang 1, 7, * , Haiping Song 1, 8 , Dayong Zheng 1, 9 , Yan Zhang 1, 10 , Min Li 2 , Jianming Xu 3 , Songlin Zhang 2 , Michael Ittmann 4 , Wenliang Li 1, 5, 6 1 Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA 2 Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA 3 Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, TX, USA 4 Department of Pathology and Immunology, Baylor College of Medicine, and Michael E. DeBakey VAMC, Houston, TX, USA 5 Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX, USA 6 Division of Oncology, Department of Internal Medicine, and Memorial Herman Cancer Center, University of Texas Health Science Center at Houston, Houston, TX, USA 7 Tumor Research Institute, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China 8 Breast and Thyroid surgery center, The Union Hospital of Tongji Medical College, Huazhong University of science and technology, Wuhan, China 9 Department of Medical Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China 10 The Union Hospital of Tongji Medical College, Huazhong University of science and technology, Wuhan, China * These authors have contributed equally to this work Corresponding to: Wenliang Li, email: wenliang.li@uth.tmc.edu Keywords: GRK3, CREB, androgen deprivation therapy, neuroendocrine prostate cancer Received: September 22, 2015 Accepted: April 23, 2016 Published: May 14, 2016 ABSTRACT Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer that commonly arises through neuroendocrine differentiation (NED) of prostate adenocarcinoma (PAC) after therapy, such as radiation therapy and androgen deprivation treatment (ADT). No effective therapeutic is available for NEPC and its molecular mechanisms remain poorly understood. We have reported that G protein-coupled receptor kinase 3 (GRK3, also called ADRBK2) promotes prostate cancer progression. In this study, we demonstrate that the ADT-activated cAMP response element binding protein (CREB) directly targets and induces GRK3. We show GRK3 expression is higher in NEPC than in PAC cells and mouse models, and it positively correlates with the expression and activity of CREB in human prostate cancers. Notably, overexpression of GRK3 in PAC cells increased the expression of NE markers in a kinase activity dependent manner. Conversely, silencing GRK3 blocked CREB-induced NED in PAC cells, reversed NE phenotypes and inhibited proliferation of NEPC cells. Taken together, these results indicate that GRK3 is a new critical activator of NE phenotypes and mediator of CREB activation in promoting NED of prostate cancer cells.