Androgen receptor mediates non-genomic activation of phosphatidylinositol 3-OH kinase in androgen-sensitive epithelial cells
Androgen receptor mediates non-genomic activation of phosphatidylinositol 3-OH kinase in androgen-sensitive epithelial cells
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DOI：
10.1074/jbc.m306143200
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发表时间：
2004-04-09
影响因子：
4.8
通讯作者：
Morel, L
中科院分区：
文献类型：
--
作者：
Baron, S;Manin, M;Morel, L
众所周知，雄激素通过与雄激素受体（AR）结合并激活靶基因的转录来调节许多细胞过程，例如细胞生长和存活。最近的数据表明，除了其配体诱导转录因子功能外，AR 还可以介导细胞核外的非转录作用。在这里，我们描述了雄激素对磷脂酰肌醇 3-OH 激酶 (PI3-K) 信号通路的转录依赖性激活。使用未转化的雄激素敏感上皮细胞，我们发现雄激素通过促进体外磷酸肌醇-3-P磷脂的积累来增强PI3-K活性。这种激活与下游激酶 AKT/蛋白激酶 B 在 Ser(473) 和 Thr(308) 残基上的时间依赖性磷酸化增加有关。激素刺激的 AKT 磷酸化需要 AR，因为与抗雄激素比卡鲁胺孵育可完全消除雄激素刺激的 AKT 磷酸化。因此，我们表明，只有在前列腺癌 PC3 细胞转染 AR 后，雄激素才会增加前列腺癌 PC3 细胞中的 AKT 磷酸化水平。下游，雄激素增强转录因子 FKHR（横纹肌肉瘤中的 Forkhead）-L1 和促凋亡 Bad 蛋白的磷酸化，并促进细胞存活，因为它们可以抵消凋亡过程。我们还报道，雄激素的非基因组效应是基于 AR 和 I(A) PI3-K 类 p85alpha 调节亚基之间的直接相互作用。总之，这些新发现指出了雄激素与控制细胞存活的 PI3-K/AKT 信号通路之间存在重要的生理相关联系。
Androgens are known to modulate many cellular processes such as cell growth and survival by binding to the androgen receptor (AR) and activating the transcription of target genes. Recent data suggested that AR can also mediate non-transcriptional actions outside the nucleus in addition to its ligand-inducible transcription factor function. Here, we describe a transcription-independent activation of the phosphatidylinositol 3-OH kinase (PI3-K) signaling pathway by androgens. Using non-transformed androgen-sensitive epithelial cells, we show that androgens enhance the PI3-K activity by promoting accumulation of phosphoinositide-3-P phospholipids in vitro. This activation is found in conjunction with an increased time-dependent phosphorylation of the downstream kinase AKT/protein kinase B on both Ser(473) and Thr(308) residues. Hormone-stimulated phosphorylation of AKT requires AR since incubation with the anti-androgen bicalutamide completely abolishes the androgen-stimulated AKT phosphorylation. Accordingly, we show that androgens increase AKT phosphorylation level in prostatic carcinoma PC3 cells only once they have been transfected with AR. Downstream, androgens enhance phosphorylation of transcription factor FKHR ( Forkhead in rhabdomyosarcoma)-L1 and proapoptotic Bad protein and promote cell survival as they can counteract an apoptotic process. We also report that non-genomic effects of androgens are based on direct interaction between AR and the p85alpha regulatory subunit of class I(A) PI3-K. Together, these novel findings point out an important and physiologically relevant link between androgens and the PI3-K/AKT signaling pathway in governing cell survival.