title: GRK3 is a direct target of CREB activation and regulates neuroendocrine differentiation of prostate cancer cells.
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.
authors.affiliation: Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.|Tumor Research Institute, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
authors.forename: Meixiang
authors.initials: M
authors.lastname: Sang
authors.affiliation: Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.|Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: Mohit
authors.initials: M
authors.lastname: Hulsurkar
authors.affiliation: Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.|Tumor Research Institute, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
authors.forename: Xiaochong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.|Breast and Thyroid surgery center, The Union Hospital of Tongji Medical College, Huazhong University of science and technology, Wuhan, China.
authors.forename: Haiping
authors.initials: H
authors.lastname: Song
authors.affiliation: Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.|Department of Medical Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Dayong
authors.initials: D
authors.lastname: Zheng
authors.affiliation: Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.|The Union Hospital of Tongji Medical College, Huazhong University of science and technology, Wuhan, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Jianming
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: Songlin
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, and Michael E. DeBakey VAMC, Houston, TX, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Ittmann
authors.affiliation: Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.|Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX, USA.|Division of Oncology, Department of Internal Medicine, and Memorial Herman Cancer Center, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: Wenliang
authors.initials: W
authors.lastname: Li
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology; D000726:Androgen Antagonists / Q000627:therapeutic use; D000818:Animals; D018278:Carcinoma, Neuroendocrine / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology*; D054770:G-Protein-Coupled Receptor Kinase 3 / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms / Q000473:pathology*
chemical_list: D000726:Androgen Antagonists; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D054770:G-Protein-Coupled Receptor Kinase 3; C517848:GRK3 protein, human
keywords: CREB; GRK3; androgen deprivation therapy; neuroendocrine prostate cancer