Caveolin-1 overexpression enhances androgen-dependent growth and proliferation in the mouse prostate
Caveolin-1 overexpression enhances androgen-dependent growth and proliferation in the mouse prostate
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DOI：
10.1016/j.biocel.2011.04.019
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发表时间：
2011-09-01
影响因子：
4
通讯作者：
Mercier, Isabelle
中科院分区：
文献类型：
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作者：
Bryant, Kelly G.;Camacho, Jeanette;Mercier, Isabelle
前列腺癌(PCA)仍然是美国男性癌症相关死亡的主要原因之一。前列腺依赖雄激素受体(AR)来调节雄激素对正常生长的影响，这种依赖在恶性前列腺生长过程中保持不变。小窝蛋白-1(Cav-1)是小窝的主要结构成分，可促进前列腺癌的恶性生长和侵袭。体外研究表明，Cav-1可以通过增强其转录活性而发挥AR共激活剂的作用。然而，Cav-1在体内如何影响雄激素依赖的生长和信号转导尚不清楚。为了探索这一作用，开发了一种新的带有激素不敏感启动子的Cav-1过表达小鼠模型。接受去势和雄激素刺激的CAV-1转基因(TG)小鼠显示出前列腺重量增加和DNA合成增加。通过基因转录和蛋白质组学分析，我们证明了Cav-1的过表达有利于雄激素调节的反应，并增强了参与转录、细胞周期进展和蛋白质合成的过程。有趣的是，Cav-1的过度表达与丝氨酸210上AR磷酸化的增加有关，这种翻译后修饰与其在雄激素刺激条件下的活性有关。此外，这些小鼠核糖体S6蛋白在丝氨酸235/236(PS6)上的磷酸化增加，丝氨酸235/236(PS6)是蛋白质合成的标志，也是mTOR途径的下游组成部分。因此，Cav-1转基因小鼠可以作为研究AR调节的参与前列腺生长和增殖的通路的新模型。(C)2011爱思唯尔有限公司。保留所有权利。
Prostate cancer (PCa) continues to be one of the leading causes of cancer-related deaths among American men. The prostate relies upon the androgen receptor (AR) to mediate the effects of androgens on normal growth, a reliance that is maintained during malignant prostate growth. Caveolin-1 (Cav-1), the main structural component of caveolae, has been shown to promote the malignant growth and invasion of prostate tumors. In vitro work has shown that Cav-1 can act as an AR coactivator by enhancing its transciptional activity. However, it is unknown how Cav-1 affects androgen-dependent growth and signaling in vivo. To explore this role, a novel mouse model of Cav-1 overexpression was developed with a hormone-insensitive promoter. Cav-1 transgenic (Tg) mice subjected to castration and androgen stimulation display enlarged prostate weights and increased DNA synthesis. Through gene transcript and proteomic profiling, we demonstrate that Cav-1 overexpression favors androgen-regulated responses and enhances processes involved in transcription, cell cycle progression and protein synthesis. Interestingly, Cav-1 overexpression was associated with an increase in the phosphorylation of AR on serine 210, a post-translational modification linked to its activity under androgen-stimulated conditions. In addition, these mice exhibited an increase in the phosphorylation of ribosomal S6 protein on serine 235/236 (pS6), a marker of protein synthesis and a downstream component of the mTOR pathway. Thus, Cav-1 Tg mice could serve as a novel model for studying AR-regulated pathways involved in prostate growth and proliferation. (C) 2011 Elsevier Ltd. All rights reserved.