PILOT PROJECT: ABSTRACT Prostate cancer (CaP) continues to be a major health problem in the US and worldwide. Available clinical and laboratory outcomes evidence a critical role for androgen receptor (AR) in both the initiation and progression to castration-resistant disease. However, despite monumental efforts spanning many decades, successful treatment of advanced CaP through the targeting of AR remains elusive, implying existence of escape mechanisms through the action of additional contributing factors. Work from our laboratory and others over the past decades has demonstrated a role for G protein-coupled receptor (GPCR) signaling and regulation of this signaling by GPCR kinases (GRKs) and their substrates in prostate carcinogenesis. Our recent observations demonstrate that GRK5, a ubiquitous S/T kinase, is expressed in human CaP cells and regulates prostate tumor growth and metastasis. Inhibition of GRK5 activity blocks CaP cell cycle progression and proliferation. Moreover, the inhibition of GRK5 activity attenuates CaP cell migration and invasion and, concordantly, increases cell attachment and focal adhesion formation. Mass spectrometry of the CaP phosphoproteome revealed the ERM protein moesin as a novel (and non-GPCR) GRK5 substrate that mediates the cell migration and invasion. The scientific goal of this program is to establish role of moesin in the GRK5-regulated prostate tumor growth and metastasis (Aim 1). The guiding hypothesis for this study is that unregulated expression/activity of GRK5 is involved in prostate tumor growth and metastasis through the regulation of moesin activity. The training goal of this research program is to provide early career minority cancer researcher (Dr. Selina Darling-Reed) with strong background in prostate cancer cell biology (Aim 2). Via the acquisition of bench skills, instruction in scientific theory and professional development, this program seeks to provide the trainee with a comprehensive set of tools necessary to launch a successful career in cancer research. Beyond the laboratory training, Dr. Darling-Reed will benefit from an outstanding environment and group of colleagues at the UF. It is anticipated that these experiences will provide her with all aspects of preparation necessary to hone a keen interest in prostate cancer research for an independent and successful academic career.
PILOT PROJECT: NARRATIVE Patients with advanced prostate cancer have limited treatment options, and progression of the disease may involve a number of complementary signaling networks. We have identified GRK5, a ubiquitous S/T kinase as a regulatory fulcrum of prostate tumor growth and metastasis. GRK5 directly phosphorylates moesin that could offer synthetic lethality drug targets to treat patients with currently incurable advanced prostate cancer.
