Downregulation of phosphodiesterase 4B (PDE4B) activates protein kinase A and contributes to the progression of prostate cancer
Downregulation of phosphodiesterase 4B (PDE4B) activates protein kinase A and contributes to the progression of prostate cancer
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DOI：
10.1002/pros.21478
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发表时间：
2012-05-01
期刊：
影响因子：
2.8
通讯作者：
Naito, Seiji
中科院分区：
文献类型：
--
作者：
Kashiwagi, Eiji;Shiota, Masaki;Naito, Seiji
背景：前列腺癌是美国男性最常见的非皮肤肿瘤。不幸的是，很少有成功的治疗去势抵抗性前列腺癌（CRPC）存在。蛋白激酶A （PKA）通路是多种正常细胞和癌细胞增殖和分化的关键介质。然而，PKA在CRPC中的活性及其调控机制尚不清楚。因此，在本研究中，我们打算揭示PKA在CRPC中的活性及其调控机制。方法采用Western blotting、实时定量聚合酶链反应、细胞毒性分析和细胞增殖实验等方法，研究PKA对前列腺癌细胞系、LNCaP及其衍生物的调控作用。结果在抗去势LNCaP衍生物（CxR细胞）中，camp特异性磷酸二酯酶4B （PDE4B）下调，PKA通路被激活。罗利普兰通过抑制PDE4B激活PKA通路，导致AR转激活，而PKA抑制剂H89则降低AR转激活。在过氧化氢和耐过氧化氢LNCaP衍生物（HPR50细胞）中，PDE4B减少，PKA活性增加。此外，PDE4B在晚期前列腺癌中的表达降低，PDE4B敲低可促进LNCaP细胞抗去势生长。结论氧化应激可抑制PDE4B的表达，激活PKA通路。PDE4B/PKA通路参与雄激素依赖性前列腺癌向CRPC的进展。这一途径可能是一种有吸引力的治疗分子靶点。前列腺癌，2012。(C) 2011 Wiley期刊公司
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. Prostate 72:741751, 2012. (C) 2011 Wiley Periodicals, Inc.