Prostaglandin E2 regulates cell migration via the intracellular activation of the epidermal growth factor receptor
Prostaglandin E2 regulates cell migration via the intracellular activation of the epidermal growth factor receptor
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DOI：
10.1074/jbc.m302474200
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发表时间：
2003-09-12
影响因子：
4.8
通讯作者：
DuBois, RN
中科院分区：
文献类型：
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作者：
Buchanan, FG;Wang, DZ;DuBois, RN
在过去的十年中，环氧合酶-2衍生的前列腺素被认为与多种癌症的发生和发展有关。最近，我们的实验室已经表明，前列腺素E-2(PGE(2))治疗可以增加结直肠癌细胞的增殖、迁移和侵袭力(盛华，H.，Shao，J.，Washington，M.K.和DuBois，R.N.(2001)J.Biol)。化学。276、18075-18081)。PGE2的刺激作用依赖于磷脂酰肌醇3-激酶/Akt通路的激活。然而，PGE2激活磷脂酰肌醇3-激酶/Akt的确切信号级联尚不清楚。在本研究中，我们证明了PGE(2)诱导的迁移和侵袭是通过表皮生长因子受体(EGFR)的快速反式激活和磷酸化而发生的。在治疗后的几分钟内，PGE2诱导Akt的激活。这种作用被EGFR特异性酪氨酸激酶抑制剂完全消除，为EGFR在这一反应中的作用提供了证据。EGFR的快速激活是通过细胞内Src介导的事件发生的，而不是通过释放细胞外的表皮生长因子样配体。通过对正常和恶性结直肠标本的直接比较，在体内也观察到了EGFR的反式激活。这些结果表明，在结肠癌的发展过程中，环氧合酶-2衍生的PGE2的早期效应部分是由EGFR介导的，这种反式激活负责随后的下游效应，包括刺激细胞迁移和侵袭。
Over the past decade cyclooxygenase-2-derived prostaglandins have been implicated in the development and progression of many types of cancer. Recently our laboratory has shown that treatment with prostaglandin E-2 (PGE(2)) induces increased proliferation, migration, and invasiveness of colorectal carcinoma cells ( Sheng, H., Shao, J., Washington, M. K., and DuBois, R. N. (2001) J. Biol. Chem. 276, 18075 - 18081). The stimulatory effects of PGE2 were dependent upon the activation of the phosphatidylinositol 3-kinase/Akt pathway. However, the exact signaling cascade responsible for phosphatidylinositol 3-kinase/Akt activation by PGE2 remains poorly defined. In the present study, we demonstrate that the PGE(2)-induced migration and invasion occurs via rapid transactivation and phosphorylation of the epidermal growth factor receptor ( EGFR). Within minutes following treatment, PGE2 induces the activation of Akt. This effect was completely abolished by EGFR-specific tyrosine kinase inhibitors providing evidence for the role of the EGFR in this response. The rapid transactivation of the EGFR occurs via an intracellular Src-mediated event but not through the release of an extracellular epidermal growth factor-like ligand. EGFR transactivation was also observed in vivo by the direct comparison of normal and malignant human colorectal samples. These results suggest that in developing colonic carcinomas, the early effects of cyclooxygenase-2- derived PGE2 are in part mediated by the EGFR, and this transactivation is responsible for subsequent downstream effects including the stimulation of cell migration and invasion.