Phosphorylated Akt Up-Regulates Angiotensin II Type-1 Receptor Expression in Castration Resistant Prostate Cancer
Phosphorylated Akt Up-Regulates Angiotensin II Type-1 Receptor Expression in Castration Resistant Prostate Cancer
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DOI：
10.1002/pros.21367
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发表时间：
2011-10-01
期刊：
影响因子：
2.8
通讯作者：
Oya, Mototsugu
中科院分区：
文献类型：
--
作者：
Kosaka, Takeo;Miyajima, Akira;Oya, Mototsugu
背景越来越多的证据表明，肾素-血管紧张素系统（RAS）参与了肿瘤血管生成的调节。我们以前证明，去势抵抗性前列腺癌（CRPC）显示出显着较高的血管紧张素II（Ang II）1型受体（AT 1 R）的表达，AT 1 R阻断（ARB）通过抑制血管生成发挥保护作用。然而，AT 1 R在CRPC中表达增加的详细分子机制尚未完全阐明。在这项研究中，我们使用C4-2和C4- 2AT 6细胞，它们是PTEN无效的、雄激素受体（AR）阳性的、产生PSA的CRPC细胞系。我们研究了磷酸化Akt（pAkt）和AT 1 R表达之间的关系，并使用LY 294002作为PI 3 K/Akt的调节剂。Western blot分析显示C4- 2AT 6细胞的pAkt表达显著高于C4-2细胞，但总Akt（tAkt）表达无显著差异。免疫组织化学（IHC）分析也揭示了从去势雄性裸鼠获得的C4- 2AT 6肿瘤中显著更高的pAkt表达。这些结果表明，C4- 2AT 6细胞获得升高的pAkt状态下雄激素消融处理在体外。用相同剂量的LY 294002处理比C4-2更有效地降低C4- 2AT 6的活力，反映了癌细胞对PI 3 K/Akt通路的依赖性。LY 294002可抑制C4- 2AT 6细胞AT 1 R的表达，且呈剂量依赖性。另一方面，在C4-2细胞中，血清饥饿诱导pAkt表达上调，从而导致AT 1 R表达增加。这些结果表明，上调pAkt有助于增加CRPC中AT 1 R的表达。前列腺71：1510-1517，2011年。(C)2011 Wiley-Liss，Inc.
Background. Accumulating evidences has suggested that the renin-angiotensin system (RAS) participates in the regulation of tumor angiogenesis. We previously demonstrated that castration-resistant prostate cancer (CRPC) showed significantly higher angiotensin II (Ang II) type-1 receptor (AT1R) expression, and that AT1R blockade (ARB) exerted protective effects by inhibiting angiogenesis. However, the detailed molecular mechanisms for the increase of AT1R expression in CRPC has not been fully elucidated yet.Methods. In this study we used C4-2 and C4-2AT6 cells, which were PTEN-null, androgen receptor (AR) positive, PSA-producing CRPC cell lines. We investigated the association between phosphorylated Akt (pAkt) and AT1R expression, and used LY294002 as a PI3K/Akt inhibitor.Results. Western blot analysis revealed C4-2AT6 cells showed significantly higher pAkt expression than C4-2 cells, although there were no significant differences in total Akt (tAkt) expression. Immunohistochemical (IHC) analysis also revealed significant higher pAkt expression in C4-2AT6 tumors obtained from castrated male nude mice. These results indicated that C4-2AT6 cells acquired elevated pAkt status under androgen-ablated treatment in vitro. Treatment with LY294002 at the same dose reduced the viability of C4-2AT6 more effectively than that of C4-2, reflecting the dependency of cancer cells on PI3K/Akt pathway. The up-regulated AT1R expression in C4-2AT6 cells was reduced by LY294002 in a dose-dependent manner. On the other hand, in C4-2 cells, serum starvation induced pAkt up-regulation, which led to an increase of AT1R expression.Conclusions. These findings indicated that up-regulation of pAkt contributed to elevated AT1R expression in CRPC. Prostate 71: 1510-1517, 2011. (C) 2011 Wiley-Liss, Inc.