A New Role for Estrogen Receptor α in Cell Proliferation and Cancer: Activating the Anticipatory Unfolded Protein Response.
A New Role for Estrogen Receptor α in Cell Proliferation and Cancer: Activating the Anticipatory Unfolded Protein Response.
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雌激素受体α在细胞增殖和癌症中的新作用：激活预期的展开的蛋白质反应。
DOI：
10.3389/fendo.2018.00325
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发表时间：
2018
影响因子：
5.2
通讯作者：
Shapiro DJ
中科院分区：
文献类型：
--
作者：
Livezey M;Kim JE;Shapiro DJ
细胞通过激活内质网（EnR）应激传感器（未折叠蛋白反应（UPR））对各种应激做出反应，包括未折叠或错误折叠蛋白的积累。UPR是高度保守的，在维持蛋白质折叠质量控制和稳态中起着关键作用。与经典的UPR激活反应模式相反，最近的研究描述了一种由蛋白质激活的预期UPR。在这一途径中，促有丝分裂激素，如雌激素（E2），表皮生长因子和血管内皮生长因子迅速激活UPR，预期未来需要增加细胞增殖后的蛋白质折叠能力。在这里，我们专注于这个最近公布的E2-雌激素受体α（ERα）的作用途径。值得注意的是，预期UPR通路的快速激活对于随后E2-ERα调节的转录程序的激活是必不可少的。此外，UPR在诊断时的激活是ERα阳性乳腺癌的一个强有力的预后标志物。此外，在含有ERα突变的细胞中，UPR被组成性激活并与抗雌激素抵抗有关，ER α突变赋予雌激素非依赖性，在转移性乳腺癌中很常见。预期性UPR的致死性ERα依赖性超激活代表了一类新的小分子ERα生物调节剂所开发的有希望的治疗方法。
Cells react to a variety of stresses, including accumulation of unfolded or misfolded protein, by activating the endoplasmic reticulum (EnR) stress sensor, the unfolded protein response (UPR). The UPR is highly conserved and plays a key role in the maintenance of protein folding quality control and homeostasis. In contrast to the classical reactive mode of UPR activation, recent studies describe a hormone-activated anticipatory UPR. In this pathway, mitogenic hormones, such as estrogen (E2), epidermal growth factor, and vascular endothelial growth factor rapidly activate the UPR in anticipation of a future need for increased protein folding capacity upon cell proliferation. Here, we focus on this recently unveiled pathway of E2-estrogen receptor α (ERα) action. Notably, rapid activation of the anticipatory UPR pathway is essential for subsequent activation of the E2-ERα regulated transcription program. Moreover, activation of the UPR at diagnosis is a powerful prognostic marker in ERα positive breast cancer. Furthermore, in cells containing ERα mutations that confer estrogen independence and are common in metastatic breast cancer, the UPR is constitutively activated and linked to antiestrogen resistance. Lethal ERα-dependent hyperactivation of the anticipatory UPR represents a promising therapeutic approach exploited by a new class of small molecule ERα biomodulator.