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

Meixiang Sang,Songlin Zhang,Haiping Song,Mohit Hulsurkar,Yan Zhang,Dayong Zheng,Xiaochong Zhang,Wenliang Li,Min Li,Michael Ittmann,Jianming Xu

doi:10.18632/oncotarget.9359

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.

Highlights

Progression to castration resistant prostate cancers (CRPC) is a major therapeutic challenge for prostate cancer patients
We show G-protein coupled receptor kinase 3 (GRK3) expression is higher in Neuroendocrine prostate cancer (NEPC) than in prostate adenocarcinoma (PAC) cells and mouse models, and it positively correlates with the expression and activity of cAMP response element binding protein (CREB) in human prostate cancers
Upon showing that GRK3 is up-regulated in NEPC as a direct target of CREB activation, we investigated whether GRK3 plays a critical role in promoting neuroendocrine differentiation (NED), induced by androgen deprivation treatment (ADT) or CREB activation

Summary

Introduction

Progression to castration resistant prostate cancers (CRPC) is a major therapeutic challenge for prostate cancer patients. The mechanisms underlying CRPC development remain largely unclear. 25% of men who die of prostate cancer have tumors with a neuroendocrine phenotype [1,2,3,4]. Neuroendocrine prostate cancer (NEPC) is characterized by loss of androgen receptor (AR) expression, resistance www.impactjournals.com/oncotarget to hormonal therapies, and elevated levels of NE-related proteins, such as enolase 2 (neuronal, ENO2) and chromogranin A and B (CHGA/CHGB) [1,2,3,4]. A better understanding of the molecular events underlying NEPC development is urgently needed to develop a therapeutic solution for CRPC/NEPC

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Conclusion