Grk3 Is A Direct Target Of Adt-Induced Creb1 Activation And It Promotes Neuroendocrine Differentiation Of Prostate Cancer Cells

Treatment-related neuroendocrine prostate cancer (t-NEPC) is an aggressive subtype of prostate cancer that is believed to arise through neuroendocrine differentiation (NED) from prostate adenocarcinoma (PAC) upon castration resistance to androgen deprivation treatment (ADT). t-NEPC is highly metastatic with poor prognosis. With the recent introduction of potent ADT drugs in clinic, the incidence of t-NEPC is expected to increase dramatically. No effective therapeutic is available for t-NEPC and its molecular mechanisms remain poorly understood. We reported that GRK3 (G protein-coupled receptor kinase 3) promotes prostate cancer progression. We further demonstrated that the ADT activates CREB1 (cAMP response element binding protein 1), which directly targets and induces GRK3. GRK3 expression is higher in t-NEPC than in PAC cells and mouse models, and it positively correlates with the expression and activity of CREB1 in human prostate cancers. Notably, overexpression of GRK3 in PAC cells increased the expression of NE markers. Conversely, silencing GRK3 blocked CREB1-induced NED in PAC cells, reversed NE phenotypes and inhibited proliferation of t-NEPC cells in culture and in xenograft. Currently, we are investigating the mechanisms underlying NEPC progression promoted by the CREB1/GRK3 axis. Taken together, these results indicate that GRK3 is a new critical activator of NE phenotypes and mediator of CREB1 activation in promoting NED of prostate cancer cells. Citation Format: Dayong Zheng, Mohit Hulsurkar, Meixiang Sang, Songlin Zhang, Jianming Xu, Martin Gleave, Michael Ittmann, Wenliang Li. GRK3 is a direct target of ADT-induced CREB1 activation and it promotes neuroendocrine differentiation of prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1577. doi:10.1158/1538-7445.AM2017-1577