Estrogen and pure antiestrogen fulvestrant (ICI 182 780) augment cell-matrigel adhesion of MCF-7 breast cancer cells through a novel G protein coupled estrogen receptor (GPR30)-to-calpain signaling axis
Estrogen and pure antiestrogen fulvestrant (ICI 182 780) augment cell-matrigel adhesion of MCF-7 breast cancer cells through a novel G protein coupled estrogen receptor (GPR30)-to-calpain signaling axis
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雌激素和纯抗雌激素氟维司群 (ICI 182 780) 通过新型 G 蛋白偶联雌激素受体 (GPR30) 至钙蛋白酶信号轴增强 MCF-7 乳腺癌细胞的细胞基质胶粘附。
DOI：
10.1016/j.taap.2014.01.005
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发表时间：
2014-03-01
影响因子：
3.8
通讯作者：
Wang, Xudong
中科院分区：
文献类型：
--
作者：
Chen, Yan;Li, Zheng;Wang, Xudong
氟维司群（ICI 182 780，ICI）已用于治疗对内分泌敏感的乳腺癌患者，但对内分泌治疗的初始或获得性耐药经常出现，特别是癌症复发转移。我们在这里证明，17-β-雌二醇（E2）和ICI增强MCF-7乳腺癌细胞与基质胶的粘附，增加钙蛋白酶1（大亚基）的自溶和粘着斑激酶（FAK）的蛋白水解，表明钙蛋白酶激活。此外，无论是E2或ICI诱导雌激素受体α的下调，而不影响G蛋白偶联雌激素受体30（GPR 30）的表达。有趣的是，GPR 30激动剂G1触发钙蛋白酶I自溶，但不触发钙蛋白酶2，而ER激动剂己烯雌酚没有引起明显的钙蛋白酶自溶。此外，E2和ICI对钙蛋白酶和细胞粘附的作用被G15或GPR 30的敲低极大地抑制。E2和ICI还诱导细胞外调节蛋白激酶1和2（ERK 1/2）的磷酸化，并且U 0126对ERK 1/2磷酸化的抑制深刻地阻碍了由雌激素和抗雌激素刺激引发的钙蛋白酶激活，表明ERK 1/2在GPR 30介导的作用中的意义。最后，钙蛋白酶特异性抑制剂ALLN或钙肽酶显著损害E2或ICI诱导的细胞粘附，表明GPR 30相关作用需要钙蛋白酶。这些数据表明，E2和ICI增强的细胞粘附通过新的GPR 30-ERK 1/2-钙蛋白酶途径发生。我们的研究结果表明，针对GPR 30信号可能是一个潜在的战略，以减少转移和提高抗雌激素治疗晚期乳腺癌的疗效。(C)版权所有© 2014 Elsevier Inc.
Fulvestrant (ICI 182 780, ICI) has been used in treating patients with hormone-sensitive breast cancer, yet initial or acquired resistance to endocrine therapies frequently arises and, in particular, cancer recurs as metastasis. We demonstrate here that both 17-beta-estradiol (E2) and ICI enhance cell adhesion to matrigel in MCF-7 breast cancer cells, with increased autolysis of calpain 1 (large subunit) and proteolysis of focal adhesion kinase (FAK), indicating calpain activation. Additionally, either E2 or ICI induced down-regulation of estrogen receptor alpha without affecting G protein coupled estrogen receptor 30 (GPR30) expression. Interestingly, GPR30 agonist G1 triggered calpain I autolysis but not calpain 2, whereas ER agonist diethylstilbestrol caused no apparent calpain autolysis. Furthermore, the actions of E2 and ICI on calpain and cell adhesion were tremendously suppressed by G15, or knockdown of GPR30. E2 and ICI also induced phosphorylation of extracellular regulated protein kinases 1 and 2 (ERK1/2), and suppression of ERK1/2 phosphorylation by U0126 profoundly impeded calpain activation triggered by estrogenic and antiestrogenic stimulations indicating implication of ERK1/2 in the GPR30-mediated action. Lastly, the E2- or ICI-induced cell adhesion was dramatically impaired by calpain-specific inhibitors, ALLN or calpeptin, suggesting requirement of calpain in the GPR30-associated action. These data show that enhanced cell adhesion by E2 and ICI occurs via a novel GPR30-ERK1/2-calpain pathway. Our results indicate that targeting the GPR30 signaling may be a potential strategy to reduce metastasis and improve the efficacy of antiestrogens in treatment of advanced breast cancer. (C) 2014 Elsevier Inc All rights reserved.