Inhibition of Rho-associated coiled-coil containing protein kinase enhances the activation of epidermal growth factor receptor in pancreatic cancer cells.
Inhibition of Rho-associated coiled-coil containing protein kinase enhances the activation of epidermal growth factor receptor in pancreatic cancer cells.
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抑制与含有蛋白激酶的Rho相关卷曲圈的抑制增强了胰腺癌细胞中表皮生长因子受体的激活。
DOI：
10.1186/1476-4598-10-79
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发表时间：
2011-07-03
期刊：
影响因子：
37.3
通讯作者：
Moriwaki H
中科院分区：
文献类型：
--
作者：
Nakashima M;Adachi S;Yasuda I;Yamauchi T;Kawaguchi J;Hanamatsu T;Yoshioka T;Okano Y;Hirose Y;Kozawa O;Moriwaki H
Rho相关卷曲螺旋蛋白激酶（Rho-kinase/ROCK）参与包括细胞增殖在内的多种细胞功能，并且通常被认为是致癌的，而一些研究表明ROCK作为癌症进展的负调节剂发挥作用。因此，岩石的确切作用仍然存在争议。我们之前曾报道过Rho-激酶/ROCK负调节SW 480结肠癌细胞中表皮生长因子（EGF）诱导的细胞增殖。在本研究中，我们研究了ROCK在胰腺癌细胞系Panc 1，KP 3和AsPc 1中EGF受体（EGFR）信号转导中的作用。在这些细胞中，Y27632，一个特定的ROCK抑制剂，增强EGF诱导的BrdU掺入。利用抗EGFR中和抗体阻断EGF刺激抑制Panc 1细胞增殖。EGF诱导RhoA活性，以及cofilin和肌球蛋白轻链（MLC）的磷酸化，这两个目标的ROCK信号，和Y27632抑制这两个过程，表明cofilin和MLC的EGF磷酸化发生通过ROCK在Panc 1细胞。当细胞用Y27632预处理或使用ROCK-siRNA进行基因沉默时，EGF诱导的EGFR酪氨酸残基磷酸化增强。我们也用转化生长因子-α得到了类似的结果。此外，EGF诱导的p44/p42丝裂原活化蛋白激酶和Akt的磷酸化也被Y27632或ROCK-siRNA增强。此外，免疫荧光显微镜研究表明，预处理与Y27632延迟EGF诱导的EGFR内化。总之，这些数据表明ROCK通过促进EGFR的内化来关闭EGFR信号传导。虽然EGF首先刺激EGFR的活化，随后增加癌细胞增殖，但EGF同时诱导ROCK的活化，然后通过负反馈系统关闭活化的EGFR途径。
Rho-associated coiled-coil containing protein kinase (Rho-kinase/ROCK) is involved in various cellular functions including cell proliferation, and is generally considered to be oncogenic, while some studies show that ROCK functions as a negative regulator of cancer progression. As a result, the precise role of ROCK remains controversial. We have previously reported that Rho-kinase/ROCK negatively regulates epidermal growth factor (EGF)-induced cell proliferation in SW480 colon cancer cells. In the present study, we investigated the role of ROCK in EGF receptor (EGFR) signaling in the pancreatic cancer cell lines, Panc1, KP3 and AsPc1. In these cells, Y27632, a specific ROCK inhibitor, enhanced EGF-induced BrdU incorporation. The blockade of EGF stimulation utilizing anti-EGFR-neutralizing antibodies suppressed Panc1 cell proliferation. EGF induced RhoA activity, as well as the phosphorylation of cofilin and myosin light chain (MLC), both targets of ROCK signaling, and Y27632 suppressed both of these processes, indicating that the phosphorylation of cofilin and MLC by EGF occurs through ROCK in Panc1 cells. EGF-induced phosphorylation of EGFR at tyrosine residues was augmented when the cells were pretreated with Y27632 or were subjected to gene silencing using ROCK-siRNA. We also obtained similar results using transforming growth factor-α. In addition, EGF-induced phosphorylation of p44/p42 mitogen-activated protein kinase and Akt were also enhanced by Y27632 or ROCK-siRNA. Moreover, an immunofluorescence microscope study revealed that pretreatment with Y27632 delayed EGF-induced internalization of EGFR. Taken together, these data indicate that ROCK functions to switch off EGFR signaling by promoting the internalization of the EGFR. While EGF first stimulates the activation of the EGFR and subsequently increases cancer cell proliferation, EGF concurrently induces the activation of ROCK, which then turns off the activated EGFR pathway via a negative feedback system.
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影响因子：
5.2
作者：
Nakashima, Masanori;Adachi, Seiji;Moriwaki, Hisataka
通讯作者：
Moriwaki, Hisataka
影响因子：
4.8
作者：
Amano, M;Ito, M;Kaibuchi, K
通讯作者：
Kaibuchi, K
影响因子：
11.2
作者：
Croft, DR;Sahai, E;Olson, MF
通讯作者：
Olson, MF
影响因子：
78.5
作者：
Massie, C;Mills, IG
通讯作者：
Mills, IG
影响因子：
254.7
作者：
Parkin, DM;Bray, F;Pisani, P
通讯作者：
Pisani, P