Macrophage inhibitory cytokine-1 activates AKT and ERK-1/2 via the transactivation of ErbB2 in human breast and gastric cancer cells
Macrophage inhibitory cytokine-1 activates AKT and ERK-1/2 via the transactivation of ErbB2 in human breast and gastric cancer cells
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DOI：
10.1093/carcin/bgn031
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发表时间：
2008-04-01
期刊：
影响因子：
4.7
通讯作者：
Lee, Jeong-Hyung
中科院分区：
文献类型：
--
作者：
Kim, Kwang-Kyu;Lee, Jung Joon;Lee, Jeong-Hyung
巨噬细胞抑制性细胞因子-1（MIC-1）是转化生长因子-β超家族的成员，其在多种人类癌症（包括乳腺癌和胃癌）中过表达。MIC-1在癌症中的功能仍然存在争议，其信号通路仍然知之甚少。在这项研究中，我们证明MIC-1诱导SK-BR-3乳腺癌细胞和SNU-216胃癌细胞中ErbB 2的反式激活。MIC-1可诱导SK-BR-3和SNU-216细胞Akt和ERK-1/2的磷酸化，并使ErbB 1、ErbB 2和ErbB 3的酪氨酸磷酸化水平升高。用ErbB 2酪氨酸激酶特异性抑制剂AG 825和AG 1478处理这些细胞，导致MIC-1诱导的Akt和ERK-1/2磷酸化的完全消除。此外，小干扰RNA介导的ErbB 2的下调不仅显著降低Akt和ERK-1/2的磷酸化，而且降低MIC-1诱导的细胞侵袭力。我们的研究结果表明，ErbB 2激活在MIC-1诱导的信号通路中起着至关重要的作用。进一步的研究表明，MIC-1通过激活哺乳动物雷帕霉素靶蛋白（mTOR）信号通路诱导缺氧诱导因子-1 α蛋白的表达及其靶基因（包括血管内皮生长因子）的表达。用MIC-1刺激SK-BR-3深刻地诱导mTOR及其下游底物（包括p70 S6 K和4 E-BP 1）的磷酸化。总的来说，这些结果表明MIC-1可能通过ErbB 2酪氨酸激酶的反式激活参与某些过表达ErbB 2的人癌细胞的恶性进展。
Macrophage inhibitory cytokine-1 (MIC-1) is a member of the transforming growth factor-beta superfamily, which is overexpressed in a variety of human cancers, including breast and gastric cancer. The function of MIC-1 in cancer remains controversial and its signaling pathways remain poorly understood. In this study, we demonstrate that MIC-1 induces the transactivation of ErbB2 in SK-BR-3 breast and SNU-216 gastric cancer cells. MIC-1 induced a significant phosphorylation of Akt and ERK-1/2, and also effected an increase in the levels of tyrosine phosphorylation of ErbB1, ErbB2 and ErbB3 in SK-BR-3 and SNU-216 cells. The treatment of these cells with AG825 and AG1478, inhibitors specific for ErbB2 tyrosine kinase, resulted in the complete abolition of MIC-1-induced Akt and ERK-1/2 phosphorylation. Furthermore, the small-interfering RNA-mediated downregulation of ErbB2 significantly reduced not only the phosphorylation of Akt and ERK-1/2 but also the invasiveness of the cells induced by MIC-1. Our results show that ErbB2 activation performs a crucial function in MIC-1-induced signaling pathways. Further investigations revealed that MIC-1 induced the expression of the hypoxia inducible factor-1 alpha protein and the expression of its target genes, including vascular endothelial growth factor, via the activation of the mammalian target of rapamycin (mTOR) signaling pathway. Stimulation of SK-BR-3 with MIC-1 profoundly induces the phosphorylation of mTOR and its downstream substrates, including p70S6K and 4E-BP1. Collectively, these results show that MIC-1 may participate in the malignant progression of certain human cancer cells that overexpress ErbB2 through the transactivation of ErbB2 tyrosine kinase.