title: G-protein coupled receptor kinase 5 regulates prostate tumor growth.
abstract: OBJECTIVE
  The limited success of cancer therapeutics is largely attributable to the ability of cancer to become resistant to conventional cytotoxic chemotherapy. Thus, further identification of signaling molecules and pathways that influence tumorigenesis is needed to increase the overall therapeutic options. GRKs, originally recognized for their conserved role in GPCR signal control, have now emerged as regulators of additional biological molecules and functions.
  
  
  METHODS
  We used Western blot analysis to determine GRK expression in prostate cancer and RNA interference to establish the role of GRK5 in prostate cancer growth and progression through the cell cycle.
  
  
  RESULTS
  GRK5 was expressed highly in the aggressive prostate cancer PC3 cell line and its silencing by RNA interference attenuated in vitro cell proliferation. PC3 cells that stably expressed lentiviral small hairpin RNA and targeted GRK5 evidence reduced xenograft tumor growth in mice. This was reversed by rescuing expression with wild-type but not with kinase inactive K215R GRK5, implying the need of GRK5 kinase activity for tumor growth. To investigate possible cellular mechanism(s) for GRK5 in cell growth regulation we tested whether kinase activity would impact cell cycle progression. Like forced over expression of kinase-inactive K215R GRK5, GRK5 knockdown led to G2/M arrest in the cell cycle. Also, evidence revealed that the loss of GRK5 activity resulted in decreased cyclin D1 expression, Rb protein phosphorylation and E2F target gene expression involved in cell cycle control.
  
  
  CONCLUSIONS
  Results provide direct evidence that GRK5 has an immediate role in the regulation of prostate tumor growth.
authors.affiliation: Department of Urology and Prostate Disease Center, University of Florida College of Medicine, Gainesville, Florida, USA.
authors.forename: Jae Il
authors.initials: JI
authors.lastname: Kim
authors.forename: Prabir
authors.initials: P
authors.lastname: Chakraborty
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Wang
authors.forename: Yehia
authors.initials: Y
authors.lastname: Daaka
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018450:Disease Progression; D054774:G-Protein-Coupled Receptor Kinase 5 / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms / Q000473:pathology*
chemical_list: D054774:G-Protein-Coupled Receptor Kinase 5