title: Downregulation of phosphodiesterase 4B (PDE4B) activates protein kinase A and contributes to the progression of prostate cancer.
abstract: BACKGROUND
  Prostate cancer is the most commonly diagnosed non-cutaneous cancer in American men. Unfortunately, few successful therapies for castration-resistant prostate cancer (CRPC) exist. The protein kinase A (PKA) pathway is a critical mediator of cellular proliferation and differentiation in various normal and cancerous cells. However, the PKA activity and the mechanism of regulation in CRPC remain unclear. Then, in this study, we intended to reveal the PKA activity and the mechanism of regulation in CRPC.
  
  
  METHODS
  Western blotting, quantitative real-time polymerase chain reaction, cytotoxicity analysis, and cell proliferation assay were used to resolve the regulatory role of PKA in prostate cancer cell line, LNCaP and their derivatives.
  
  
  RESULTS
  cAMP-specific phosphodiesterase 4B (PDE4B) was downregulated and the PKA pathway was activated in castration-resistant LNCaP derivatives (CxR cells). Rolipram activated the PKA pathway via inhibition of PDE4B, resulting in AR transactivation while the PKA inhibitor, H89 reduced AR transactivation. In response to hydrogen peroxide and in hydrogen peroxide-resistant LNCaP derivatives (HPR50 cells) PDE4B was decreased and as a result PKA activity was increased. Moreover, PDE4B expression was reduced in advanced prostate cancer and PDE4B knockdown promoted castration-resistant growth of LNCaP cells.
  
  
  CONCLUSIONS
  Oxidative stress may suppress PDE4B expression and activate the PKA pathway. The PDE4B/PKA pathway contributed to progression of androgen-dependent prostate cancer to CRPC. This pathway may represent an attractive therapeutic molecular target.
authors.affiliation: Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Kashiwagi
authors.forename: Masaki
authors.initials: M
authors.lastname: Shiota
authors.forename: Akira
authors.initials: A
authors.lastname: Yokomizo
authors.forename: Momoe
authors.initials: M
authors.lastname: Itsumi
authors.forename: Junichi
authors.initials: J
authors.lastname: Inokuchi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Uchiumi
authors.forename: Seiji
authors.initials: S
authors.lastname: Naito
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000096:biosynthesis / Q000378:metabolism*; D018450:Disease Progression; D015536:Down-Regulation; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020889:Rolipram / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D007546:Isoquinolines; D058988:Phosphodiesterase 4 Inhibitors; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D006861:Hydrogen Peroxide; D017868:Cyclic AMP-Dependent Protein Kinases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517360:PDE4B protein, human; D020889:Rolipram; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide