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Cyclin-Dependent Kinase Inhibitor suppresses the growth in oral squamous cell carcinoma cells

细胞周期蛋白依赖性激酶抑制剂抑制口腔鳞状细胞癌细胞的生长

基本信息

批准号：
12671938
负责人：
SHINTANI Satoru
金额：
$ 2.18万
依托单位：
Ehime University (2001)Okayama University (2000)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

项目摘要

Cyclin-dependent kinases (CDKs) play an essential role in intracellular control of cell cycle. CDK inhinitors (Flavopiridol and Roscpvitine) that inhibits tumor growth in vitro and in vivo by because of the inhibiting CDKs. These agents are known to inhibit CDK2, CDK4 and CDK7 activities, to diminish cyclin Dl expressions, and to induce apoptosis. However, effects of CDK inhibitors against oral squamous cell carcinoma (OSCC) cells and mechanisms of these agents mediated cytotoxicity have not been fully elucidated.In this study, we have investigated effects of CDK inhibitors in OSCC cell lines and studied mechanisms of CDK inhibitors mediated-apoptosis. CDK inhibitors were found to inhibit the growth of all five OSCC cells in time and dose-dependent manner and to diminish CDKs activities. Induction of apoptosis was observed in all cells, as well as cells with sub-Gl DNA contents, DNA fragmentations, and PARP cleavages. No alternation of expression levels of Bcl-2, an apoptosis regulator was observed. In contrast, Bcl-XL was down regulated and Bcl-Xs was up regulated after being exposed to CDK inhibitors. CDK inhibitors treatments also resulted in remarkable reductions of cyclin A, cyclin B, and cyclin Dl expressions in OSCC cells. We also found that expression levels of CDK Activation Kinase and CDC25C were reduced, and p34 CDK2 that phosphorylated in Thr 14 and Tyr 15: inactive form were up-regulated after CDK inhibitors exposure.Our data indicate that CDK inhibitors has growth inhibition activities against OSCC in vitro. CDK inhibitors not only inhibits CDKs directly, but it also inhibits CDKs activation pathway and activates Bcl-X apoptotic pathway.

细胞周期蛋白依赖性激酶（Cyclin-dependent kinases，CDKs）在细胞周期调控中起重要作用。CDK抑制剂（Flavopiridol和Roscpvitine）通过抑制CDK在体外和体内抑制肿瘤生长。已知这些药物可抑制CDK 2、CDK 4和CDK 7活性，减少细胞周期蛋白D1表达并诱导细胞凋亡。然而，CDK抑制剂对口腔鳞状细胞癌（oral squamous cell carcinoma，OSCC）细胞的杀伤作用及其机制尚未完全阐明，本研究通过观察CDK抑制剂对OSCC细胞的作用，探讨CDK抑制剂介导OSCC细胞凋亡的机制。CDK抑制剂可抑制所有5种OSCC细胞的生长，并呈时间和剂量依赖性，同时降低CDK活性。在所有细胞以及具有亚G1 DNA含量、DNA片段化和PARP裂解的细胞中观察到细胞凋亡诱导。未观察到凋亡调节因子Bcl-2表达水平的改变。与此相反，在暴露于CDK抑制剂后，Bcl-XL下调，Bcl-Xs上调。CDK抑制剂处理还导致OSCC细胞中细胞周期蛋白A、细胞周期蛋白B和细胞周期蛋白D1表达的显著降低。CDK抑制剂作用后，CDK活化激酶和CDC 25 C的表达水平降低，磷酸化的Thr 14和Tyr 15失活形式的p34 CDK 2表达上调，提示CDK抑制剂对口腔鳞癌具有体外生长抑制作用。CDK抑制剂不仅可以直接抑制CDK，还可以抑制CDK活化途径，激活Bcl-X凋亡途径。