A positive feedback between activated extracellularly regulated kinase and cyclooxygenase/lipoxygenase maintains proliferation and migration of breast cancer cells.
A positive feedback between activated extracellularly regulated kinase and cyclooxygenase/lipoxygenase maintains proliferation and migration of breast cancer cells.
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DOI：
10.1210/en.2008-0616
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发表时间：
2009-04
期刊：
影响因子：
4.8
通讯作者：
J. You;Da Mi;Xiaolei Zhou;L. Qiao;Hang Zhang;Xiao-dong Zhang;L. Ye
中科院分区：
文献类型：
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作者：
J. You;Da Mi;Xiaolei Zhou;L. Qiao;Hang Zhang;Xiao-dong Zhang;L. Ye
乳腺癌细胞的转移是乳腺癌患者死亡的主要原因。为什么具有高转移潜能的乳腺癌细胞总是保持高增殖和迁移？与肿瘤转移相关的内源性信号通路仍不清楚。在本研究中，我们解决ERK和花生四烯酸（AA）代谢相关的酶之间的联系是否有助于乳腺癌细胞的增殖和迁移。为了确定参与维持乳腺癌细胞增殖和迁移的内源性信号通路，我们对转移潜力不同的人乳腺癌细胞系进行了平行研究。我们的数据显示，具有高转移潜力的细胞系，包括LM-MCF-7和MDA-MB-231，相对于MCF-7细胞，表现出显著高的、持续的磷酸化ERK（pERK）1/2水平。我们的研究结果表明，β-连环蛋白，细胞周期蛋白D1，和生存素作为下游效应的pERK 1/2，而Gi/o蛋白，磷脂酶C，和蛋白激酶C作为上游激活剂的pERK 1/2。此外，AA代谢物能够通过环氧合酶和脂氧合酶激活Gi/o蛋白、磷脂酶C、蛋白激酶C和pERK 1/2级联。相反，活化的ERK 1/2通过正反馈环促进AA代谢，这有助于乳腺癌细胞的高增殖潜力和迁移。总之，我们的数据提供了新的机制的见解，可能的内源性信号转移信号通路参与维持乳腺癌细胞的增殖和迁移。
Metastasis of breast cancer cells is the leading cause of death in breast cancer patients. Why do breast cancer cells with high metastatic potential always keep in high proliferation and migration? The endogenous signaling pathways associated with tumor metastasis remain unclear. In the present study, we address whether a link between ERK and the enzymes associated with arachidonic acid (AA) metabolism contributes to the proliferation and migration of breast cancer cells. To identify endogenous signaling pathways involved in sustaining proliferation and migration of breast cancer cells, we performed parallel studies of human breast cancer cell lines that differ in their metastatic potential. Our data showed that cell lines with high metastatic potential, including LM-MCF-7 and MDA-MB-231, exhibited significantly high, sustained levels of phosphorylated ERK (pERK) 1/2 relative to MCF-7 cells. Our findings showed that beta-catenin, cyclin D1, and survivin serve downstream effectors of pERK1/2, whereas Gi/o proteins, phospholipase C, and protein kinase C serve upstream activators of pERK1/2. In addition, AA metabolites were able to activate Gi/o proteins, phospholipase C, protein kinase C, and pERK1/2 cascades through cyclooxygenase and lipoxygenase. In contrast, activated ERK1/2 promoted AA metabolism through a positive feedback loop, which conduces to a high proliferative potential and the migration of the breast cancer cells. Together, our data provide new mechanistic insights into possible endogenous signaling metastatic signaling pathways involved in maintaining proliferation and migration of breast cancer cells.