sMEK1 enhances gemcitabine anti-cancer activity through inhibition of phosphorylation of Akt/mTOR
sMEK1 enhances gemcitabine anti-cancer activity through inhibition of phosphorylation of Akt/mTOR
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DOI：
10.1007/s10495-012-0751-0
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发表时间：
2012-10-01
期刊：
影响因子：
7.2
通讯作者：
Rho, Seung Bae
中科院分区：
文献类型：
--
作者：
Byun, Hyun-Jung;Kim, Boh-Ram;Rho, Seung Bae
最近，我们报道了sMEK 1在癌细胞和组织中下调，并且它作为一种新的促凋亡蛋白增强促增殖作用。然而，sMEK 1肿瘤抑制因子在细胞信号通路中的生物学机制尚未得到很好的理解。在我们目前的工作中，我们研究了sMEK 1是否可以促进吉西他滨在人卵巢癌系统中的细胞毒活性。最初，我们尝试使用吉西他滨传统化疗剂和OVCAR-3癌细胞中sMEK 1过表达的治疗。sMEK 1和吉西他滨的联合治疗在抑制细胞增殖方面比单独的任一化疗剂治疗更有效。此外，sMEK 1通过其在肿瘤发生中促进吉西他滨抑制的细胞迁移的能力积极促进细胞迁移。细胞周期相关蛋白与细胞周期蛋白D1和CDK 4的下调以及作为细胞周期蛋白依赖性激酶抑制剂的p16和p27的促进高度相关。同时，sMEK 1将细胞周期进程阻滞在G（1）-G（0）期，并激活p53和p21表达，而Bcl-2和Bcl-xL蛋白表达降低。此外，sMEK 1和吉西他滨抑制PI 3 K下游信号调节剂（如PDK 1和Akt）的磷酸化。p53和p21启动子荧光素酶活性被sMEK 1或吉西他滨促进，并且sMEK 1和吉西他滨组合进一步相加激活启动子。此外，正如预期的那样，sMEK 1加吉西他滨显著降低了p70 S6 K的磷酸化和4 E-BP 1的磷酸化，这是mTOR复合物级联的最佳表征的靶标之一。综上所述，这些结果提供了证据表明，sMEK 1可以通过上调p53表达有效地调节吉西他滨的促凋亡活性。
Recently, we reported that sMEK1 is down-regulated in cancer cells and tissues, and that it enhances the pro-proliferative effect as a novel pro-apoptotic protein. However, the biological mechanism of the sMEK1 tumor suppressor in the cellular signal pathway has not been well understood. In our current work, we examined whether sMEK1 could promote the cytotoxic activity of gemcitabine in the human ovarian carcinoma system. Initially, we attempted to use a treatment of gemcitabine traditional chemotherapeutic agent and over-expression of sMEK1 in OVCAR-3 cancer cells. The combined treatment of sMEK1 and gemcitabine was more effective at inhibiting cell proliferation than either chemotherapeutic agent treatment alone. In addition, sMEK1 actively contributes to cell migration through its ability to promote gemcitabine-inhibited cell migration in tumorigenesis. Cell cycle-related proteins are highly associated with the down-regulation of cyclin D1 and CDK4, and the promotion of p16 and p27 as a cyclin-dependent kinase inhibitor. At the same time, sMEK1 arrests cell cycle progression in the G(1)-G(0) phase, and activates p53 and p21 expression, whereas Bcl-2 and Bcl-xL protein expression is reduced. Additionally, sMEK1 and gemcitabine suppresses the phosphorylation of signaling modulators downstream of PI3K, such as PDK1 and Akt. The p53 and p21 promoter luciferase activities were promoted by either sMEK1 or gemcitabine, and sMEK1 and gemcitabine combined additively activated the promoter further. Furthermore, as expected, sMEK1 plus gemcitabine markedly reduced the phosphorylation of p70S6K and the phosphorylation of 4E-BP1, which is one of the best characterized targets of the mTOR complex cascade. Taken together, these results provide evidence that sMEK1 can effectively regulate the pro-apoptotic activity of gemcitabine through the up-regulation of p53 expression.