CCL2/CCR2 Chemokine Signaling Coordinates Survival and Motility of Breast Cancer Cells through Smad3 Protein- and p42/44 Mitogen-activated Protein Kinase (MAPK)-dependent Mechanisms
CCL2/CCR2 Chemokine Signaling Coordinates Survival and Motility of Breast Cancer Cells through Smad3 Protein- and p42/44 Mitogen-activated Protein Kinase (MAPK)-dependent Mechanisms
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DOI：
10.1074/jbc.m112.365999
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发表时间：
2012-10-19
影响因子：
4.8
通讯作者：
Cheng, Nikki
中科院分区：
文献类型：
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作者：
Fang, Wei Bin;Jokar, Iman;Cheng, Nikki
细胞活力和存活增加是转移性肿瘤细胞的重要标志。然而，调控这些细胞过程之间相互作用的机制仍然知之甚少。在这些研究中，我们证明了CCL2，一种众所周知的调节免疫细胞迁移的趋化因子，在乳腺癌细胞的信号传导中起重要作用。我们报告了在一组小鼠和人类乳腺癌细胞系中，CCL2通过增加Smad3和p42/44MAPK蛋白磷酸化来增强细胞迁移和存活。发现G蛋白偶联受体CCR2在乳腺癌中升高，与CCL2表达相关。RNA干扰乳腺癌细胞中CCR2的表达可显著抑制CCR2诱导的迁移、存活以及Smad3和p42/44MAPK蛋白的磷酸化。乳腺癌细胞中Smad3表达的中断阻断了ccl2诱导的细胞存活和迁移，并部分降低了p42/44MAPK的磷酸化。MEK抑制剂U0126在smad3缺陷细胞中消融MAPK磷酸化进一步降低了细胞存活，但没有迁移。这些数据表明，Smad3通过MEK-p42/44MAPK信号传导调节CCL2诱导的细胞运动和存活，而CCL2诱导独立于Smad3的MEK-p42/44MAPK信号传导是细胞存活的另一种机制。此外，我们发现ccl2诱导的Smad3信号通过MEK-p42/44MAPK调控Rho GTPase的表达和活性，介导ccl2诱导的乳腺癌细胞运动和存活。通过这些研究，我们描述了CCL2/CCR2趋化因子信号在调节乳腺癌细胞运动和生存之间的内在关系以及转移过程中的重要作用。
Increased cell motility and survival are important hallmarks of metastatic tumor cells. However, the mechanisms that regulate the interplay between these cellular processes remain poorly understood. In these studies, we demonstrate that CCL2, a chemokine well known for regulating immune cell migration, plays an important role in signaling to breast cancer cells. We report that in a panel of mouse and human breast cancer cell lines CCL2 enhanced cell migration and survival associated with increased phosphorylation of Smad3 and p42/44MAPK proteins. The G protein-coupled receptor CCR2 was found to be elevated in breast cancers, correlating with CCL2 expression. RNA interference of CCR2 expression in breast cancer cells significantly inhibited CCL2-induced migration, survival, and phosphorylation of Smad3 and p42/44MAPK proteins. Disruption of Smad3 expression in mammary carcinoma cells blocked CCL2-induced cell survival and migration and partially reduced p42/44MAPK phosphorylation. Ablation of MAPK phosphorylation in Smad3-deficient cells with the MEK inhibitor U0126 further reduced cell survival but not migration. These data indicate that Smad3 signaling through MEK-p42/44MAPK regulates CCL2-induced cell motility and survival, whereas CCL2 induction of MEK-p42/44MAPK signaling independent of Smad3 functions as an alternative mechanism for cell survival. Furthermore, we show that CCL2-induced Smad3 signaling through MEK-p42/44MAPK regulates expression and activity of Rho GTPase to mediate CCL2-induced breast cancer cell motility and survival. With these studies, we characterize an important role for CCL2/CCR2 chemokine signaling in regulating the intrinsic relationships between breast cancer cell motility and survival with implications on the metastatic process.