Rho-kinase regulates negatively the epidermal growth factor-stimulated colon cancer cell proliferation
Rho-kinase regulates negatively the epidermal growth factor-stimulated colon cancer cell proliferation
复制标题
DOI：
10.3892/ijo_00000533
复制
发表时间：
2010-03-01
影响因子：
5.2
通讯作者：
Moriwaki, Hisataka
中科院分区：
文献类型：
--
作者：
Nakashima, Masanori;Adachi, Seiji;Moriwaki, Hisataka
已有研究表明Rho和Rho激酶参与肌动蛋白细胞骨架的组装，并与人类肿瘤的发生和发展有关。然而，Rho/Rho激酶途径参与细胞周期进程的机制尚未得到精确表征。在这项研究中，我们研究了Rho激酶在表皮生长因子（EGF）信号转导在SW 480结肠癌细胞中的作用。我们发现，Y27632，Rho激酶抑制剂，剂量依赖性地诱导这些细胞的细胞增殖。利用抗EGF受体中和抗体阻断EGF刺激显著抑制细胞生长，表明EGF刺激在SW 480细胞中的细胞增殖中起重要作用。我们还发现EGF诱导Rho激酶活化。有趣的是，当细胞用Y27632或法舒地尔（另一种Rho激酶抑制剂）预处理时，EGF诱导的Akt和糖原合成酶激酶-3 β（GSK-3 β）磷酸化，而不是p44/p42丝裂原活化蛋白（MAP）激酶磷酸化，呈剂量依赖性增强。此外，虽然EGF增加视网膜母细胞瘤肿瘤抑制蛋白的磷酸化以及细胞周期蛋白D1蛋白的表达水平，预处理与Y2.7632加速他们。总之，我们的研究结果表明，Rho激酶负调控EGF诱导的细胞增殖上游的Akt/GSK-3 β在结肠癌细胞。
It has been reported that Rho and Rho-kinase are involved in actin cytoskeleton organization and associated with carcinogenesis and progression of human cancers. However, the mechanism how the Rho/Rho-kinase pathway is involved in cell cycle progression has not been precisely characterized. In this study, we investigated the role of Rho-kinase in epidermal growth factor (EGF) signaling in SW480 colon cancer cells. We found that Y27632, a Rho-kinase inhibitor, dose-dependently induced cell proliferation in these cells. The blockade of EGF stimulation utilizing anti-EGF receptor neutralizing antibodies significantly suppressed cell growth, suggesting that EGF stimulation plays an important role in cell proliferation in SW480 cells. We also found that EGF induced Rho-kinase activation. Interestingly, EGF-induced phosphorylation of both Akt and glycogen synthase kinase-3 beta (GSK-3 beta), but not p44/p42 mitogen-activated protein (MAP) kinase, were dose-dependently enhanced when the cells were pretreated with Y27632 or fasudil, another Rho-kinase inhibitor. Moreover, whereas EGF increased the phosphorylation of retinoblastoma tumor suppressor protein as well as cyclin D1 protein expression level, pretreatment with Y2.7632 accelerated them. Taken together, our results suggest that Rho-kinase regulates negatively EGF-induced cell proliferation upstream of Akt/GSK-3 beta in colon cancer cells.