Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor α -: A new model for anti-estrogen resistance
Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor α -: A new model for anti-estrogen resistance
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DOI：
10.1074/jbc.m010840200
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发表时间：
2001-03-30
影响因子：
4.8
通讯作者：
Nakshatri, H
中科院分区：
文献类型：
--
作者：
Campbell, RA;Bhat-Nakshatri, P;Nakshatri, H
雌激素受体（ER）通过与靶基因启动子区的雌激素反应元件结合或通过蛋白质-蛋白质相互作用介导乳腺和子宫上皮细胞中雌激素的大部分生物学效应。抗雌激素药物如他莫昔芬通过减少雌激素调节基因的表达来抑制ER阳性乳腺癌的生长。然而，ER阳性肿瘤的抗雌激素抗性生长仍然是一个重要的临床问题。在这里，我们表明，磷脂酰肌醇（PI）3-激酶和AKT激活ER α在雌激素缺乏。尽管PI 3-激酶增加ER α的雌激素非依赖性激活功能1（AF-1）和雌激素依赖性激活功能2（AF-2）的活性，但AKT仅增加AF-1的活性，PTEN和无催化活性的AKT降低PI 3-激酶诱导的AF-1活性，表明PI I-激酶在激活ER α中利用AKT依赖性和AKT非依赖性途径。ER α的共有AKT磷酸化位点Ser-167是AKT磷酸化和激活所必需的。此外，PI 3-激酶/AKT通路的特异性抑制剂LY 294002在体内降低ER α的磷酸化。此外，AKT过表达导致雌激素调节的pS2基因、Bcl-2和巨噬细胞抑制性细胞因子1的上调。我们证明，AKT保护乳腺癌细胞免受他莫昔芬诱导的凋亡。总之，这些结果确定了PI 3-激酶/AKT存活途径的激活、ER α的非依赖性激活和他莫昔芬诱导的凋亡消退的抑制之间的分子联系。
Estrogen receptors (ERs) mediate most of the biological effects of estrogen in mammary and uterine epithelial cells by binding to estrogen response elements in the promoter region of target genes or through protein-protein interactions. Anti-estrogens such as tamoxifen inhibit the growth of ER-positive breast cancers by reducing the expression of estrogen-regulated genes. However, anti-estrogen-resistant growth of ER-positive tumors remains a significant clinical problem. Here we show that phosphatidylinositol (PI) 3-kinase and AKT activate ER alpha in the absence of estrogen. Although PI 3-kinase increased the activity of both estrogen-independent activation function 1 (AF-1) and estrogen-dependent activation function 2 (AF-2) of ER alpha, AKT increased the activity of only AF-1, PTEN and a catalytically inactive AKT decreased PI 3-kinase-induced AF-1 activity, suggesting that PI I-kinase utilizes AKT-dependent and AKT-independent pathways in activating ER alpha. The consensus AKT phosphorylation site Ser-167 of ER alpha is required for phosphorylation and activation by AKT, In addition, LY294002, a specific inhibitor of the PI 3-kinase/AKT pathway, reduced phosphorylation of ER alpha in vivo, Moreover, AKT overexpression led to up-regulation of estrogen-regulated pS2 gene, Bcl-2, and macrophage inhibitory cytokine 1. We demonstrate that AKT protects breast cancer cells from tamoxifen-induced apoptosis. Taken together, these results define a molecular link between activation of the PI3-kinase/AKT survival pathways, hormone-independent activation of ER alpha, and inhibition of tamoxifen-induced apoptotic regression.