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.
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: Rodrigo B de Alexandre; Anelia D Horvath; Eva Szarek; Allison D Manning; Leticia F Leal; Fabio Kardauke; Jonathan A Epstein; Dirce M Carraro; Fernando A Soares; Tatiyana V Apanasovich; Constantine A Stratakis; Fabio R Faucz Journal: Endocr Relat Cancer Date: 2015-05-15 Impact factor: 5.678
Authors: Scott R Bauer; Erin L Richman; Eduardo Sosa; Vivian Weinberg; Xiaoling Song; John S Witte; Peter R Carroll; June M Chan Journal: Prostate Date: 2013-08-29 Impact factor: 4.104
Authors: Sharadindu Shil; R S Joshi; C G Joshi; A K Patel; Ravi K Shah; Namrata Patel; Subhash J Jakhesara; Sumana Kundu; Bhaskar Reddy; P G Koringa; D N Rank Journal: Vet World Date: 2017-01-13
Authors: Jennifer K Pleiman; Amy A Irving; Zhishi Wang; Erik Toraason; Linda Clipson; William F Dove; Dustin A Deming; Michael A Newton Journal: PLoS Genet Date: 2018-09-06 Impact factor: 5.917