Phosphatidylinositol 3-kinase/Akt stimulates androgen pathway through GSK3beta inhibition and nuclear beta-catenin accumulation.
Phosphatidylinositol 3-kinase/Akt stimulates androgen pathway through GSK3beta inhibition and nuclear beta-catenin accumulation.
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发表时间：
2002
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通讯作者：
Manju Sharma;W. W. Chuang-W.;Zijie Sun
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作者：
Manju Sharma;W. W. Chuang-W.;Zijie Sun
PI 3 K/Akt在前列腺癌细胞生长和存活中起关键作用。最近的研究表明，PI 3 K/Akt在前列腺细胞中的作用是通过雄激素信号传导介导的。PI 3 K抑制剂LY 294002和肿瘤抑制剂PTEN负调节PI 3 K/Akt通路并抑制AR活性。然而，PI 3 K/Akt和PTEN调节雄激素途径的分子机制目前尚不清楚。在这里，我们证明，阻断PI 3 K/Akt通路减少了内源性AR靶基因的表达。此外，我们发现LY 294002对AR活性的抑制是通过磷酸化和失活GSK 3 β介导的，GSK 3 β是PI 3 K/Akt的下游底物，其导致β-连环蛋白在核中积累。鉴于最近的证据表明β-连环蛋白作为AR的共激活剂，我们的研究结果表明PI 3 K/Akt调节雄激素信号的新机制。在PTEN缺失的前列腺癌细胞系中，我们发现PTEN表达降低了β-连环蛋白介导的AR反式激活增强。使用β-连环蛋白的突变体，我们进一步证明了PTEN的抑制作用是由GSK 3 β调节的β-连环蛋白降解介导的。我们的研究结果描绘了PI 3 K，wnt和雄激素通路之间的新联系，并提供了新的见解前列腺肿瘤的发展和进展的机制。
PI3K/Akt plays a critical role in prostate cancer cell growth and survival. Recent studies have shown that the effect of PI3K/Akt in prostate cells is mediated through androgen signaling. The PI3K inhibitor, LY294002, and a tumor suppressor, PTEN, negatively regulate the PI3K/Akt pathway and repress AR activity. However, the molecular mechanisms whereby PI3K/Akt and PTEN regulate the androgen pathway are currently unclear. Here, we demonstrate that blocking the PI3K/Akt pathway reduces the expression of an endogenous AR target gene. Moreover, we show that the repression of AR activity by LY294002 is mediated through phosphorylation and inactivation of GSK3beta, a downstream substrate of PI3K/Akt, which results in the nuclear accumulation of beta-catenin. Given the recent evidence that beta-catenin acts as a coactivator of AR, our findings suggest a novel mechanism by which PI3K/Akt modulates androgen signaling. In a PTEN-null prostate cancer cell line, we show that PTEN expression reduces beta-catenin-mediated augmentation of AR transactivation. Using the mutants of beta-catenin, we further demonstrate that the repressive effect of PTEN is mediated by a GSK3beta-regulated degradation of beta-catenin. Our results delineate a novel link among the PI3K, wnt, and androgen pathways and provide fresh insights into the mechanisms of prostate tumor development and progression.