Tamoxifen treatment promotes phosphorylation of the adhesion molecules, p130Cas/BCAR1, FAK and Src, via an adhesion-dependent pathway
Tamoxifen treatment promotes phosphorylation of the adhesion molecules, p130Cas/BCAR1, FAK and Src, via an adhesion-dependent pathway
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DOI：
10.1038/sj.onc.1209747
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发表时间：
2006-12-07
期刊：
影响因子：
8
通讯作者：
O'Neill, G. M.
中科院分区：
文献类型：
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作者：
Cowell, L. N.;D Graham, J.;O'Neill, G. M.
粘附相关分子p130 Cas/BCAR 1促进对他莫昔芬的耐药性的报道表明，粘附介导的信号传导可能会被他莫昔芬治疗改变。我们发现p130 Cas/BCAR 1磷酸化在他莫昔芬处理的雌激素受体（ER）阳性MCF-7乳腺癌细胞中增强。雌激素和他莫昔芬的作用进行了评估独立和组合，结果表明，他莫昔芬拮抗雌激素调节p130 Cas/BCAR 1磷酸化。磷酸化与他莫昔芬雌激素受体拮抗剂作用相关，因为磷酸化作用被纯抗雌激素ICI复制182，780。相应地，在暴露于他莫昔芬的ER阴性细胞中，磷酸化没有改变。我们发现，删除p130 Cas/BCAR 1底物结构域大大减少了他莫昔芬诱导的p130 Cas/BCAR 1磷酸化，并赋予增强的敏感性，他莫昔芬。P130 Cas/BCAR 1与粘着斑激酶（FAK）和Src激酶形成磷酸化依赖性信号传导复合物，其促进粘附介导的细胞存活。因此，我们研究了p130 Cas/BCAR 1，Src和FAK磷酸化在14天时间过程中的动力学，并发现这些分子在暴露于他莫昔芬7天后持续磷酸化。Src激酶的抑制显示减少他莫昔芬促进的p130 Cas/BCAR 1磷酸化并降低细胞活力。在他莫昔芬处理的MCF-7细胞中，Src/FAK/p130 Cas/BCAR 1粘附信号通路的刺激不会引起迁移增加;然而，存在细胞存活分子Akt的Src依赖性磷酸化。相应地，Akt抑制降低了用他莫昔芬处理的细胞中的细胞活力。我们建议，延长激活的粘附依赖性信号可能会赋予一个生存优势，在响应额外的细胞侮辱，或者，可能会平衡细胞发展一个迁移表型响应额外的细胞线索。
Reports that the adhesion-associated molecule p130Cas/BCAR1 promotes resistance to tamoxifen suggested that adhesion-mediated signalling may be altered by tamoxifen treatment. We find that p130Cas/BCAR1 phosphorylation is enhanced in tamoxifen-treated estrogen receptor (ER)positive MCF-7 breast cancer cells. The effects of estrogen and tamoxifen were assessed independently and in combination, and the results demonstrate that tamoxifen antagonizes estrogen regulation of p130Cas/BCAR1 phosphorylation. Phosphorylation correlates with tamoxifen ER antagonist effects, as phosphorylation effects are replicated by the pure antiestrogen ICI 182, 780. Correspondingly, phosphorylation is not changed in ER-negative cells exposed to tamoxifen. We show that deletion of the p130Cas/BCAR1 substrate domain substantially reduces tamoxifen-induced phosphorylation of p130Cas/BCAR1 and confers enhanced sensitivity to tamoxifen. P130Cas/BCAR1 forms a phosphorylation-dependent signalling complex with focal adhesion kinase (FAK) and Src kinase that promotes adhesion-mediated cell survival. Therefore, we examined the kinetics of p130Cas/BCAR1, Src and FAK phosphorylation over a 14-day time course and find sustained phosphorylation of these molecules after 7 days exposure to tamoxifen. Inhibition of Src kinase is shown to reduce tamoxifen-promoted p130Cas/BCAR1 phosphorylation and reduce cell viability. Stimulation of the Src/FAK/p130Cas/BCAR1 adhesion signalling pathway in tamoxifen-treated MCF-7 cells does not cause increased migration; however, there is Src-dependent phosphorylation of the cell survival molecule Akt. Correspondingly, Akt inhibition reduces cell viability in cells treated with tamoxifen. We propose that prolonged activation of adhesion-dependent signalling may confer a survival advantage in response to additional cellular insults or alternatively, may poise cells to develop a migratory phenotype in response to additional cellular cues.