3-Phosphoinositide-Dependent Protein Kinase-1 Regulates Proliferation and Survival of Cancer Cells with an Activated Mitogen-Activated Protein Kinase Pathway
3-Phosphoinositide-Dependent Protein Kinase-1 Regulates Proliferation and Survival of Cancer Cells with an Activated Mitogen-Activated Protein Kinase Pathway
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DOI：
10.1158/1541-7786.mcr-09-0179
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发表时间：
2010-03-01
影响因子：
5.2
通讯作者：
Boyapati, Anita
中科院分区：
文献类型：
--
作者：
Lu, Zhuomei;Cox-Hipkin, Mary Ann;Boyapati, Anita
胰岛素和生长因子与细胞表面受体酪氨酸激酶的结合激活磷脂酰肌醇3-激酶（PI 3 K）并产生第二信使磷脂酰肌醇3，4，5-三磷酸。该第二信使导致3-磷酸肌醇依赖性蛋白激酶-1（PDK 1）募集到质膜的近端，这导致AKT激酶的活化。此外，PDK 1可以磷酸化许多其他激酶，包括p90 RSK，一种对细胞增殖和存活很重要的促分裂原活化蛋白激酶（MAPK）下游的激酶。以前的研究表明，PDK 1的丢失使肿瘤细胞对化疗药物和放射敏感，但没有集中于描绘PDK 1对与PI 3 K/AKT通路以外的各种癌症相关的通路特异性突变的贡献。在这项研究中，我们表明，在MAPK通路中激活的黑色素瘤和结肠癌细胞系中，RNAi减少PDK 1导致显著的细胞生长抑制和细胞凋亡。此外，肿瘤细胞中PDK 1的减少导致PAK激酶信号传导受损，肌动蛋白聚合改变，细胞迁移减少。这些研究表明，PDK 1在肿瘤细胞中的MAPK和PI 3 K信号转导中起着关键作用。Mol Cancer Res; 8（3）; 421-32.（C）2010年AACR。
Engagement of cell surface receptor tyrosine kinases by insulin and growth factors activates phosphatidylinositol 3-kinase (PI3K) and generates the second messenger, phosphatidylinositol 3,4,5-trisphosphate. This second messenger leads to the recruitment of 3-phosphoinositide-dependent protein kinase-1 (PDK1) to the proximal side of the plasma membrane, which results in the activation of AKT kinase. In addition, PDK1 can phosphorylate numerous other kinases, including p90RSK, a kinase downstream of mitogen-activated protein kinase (MAPK) that is important for cell proliferation and survival. Previous studies have shown that the loss of PDK1 sensitizes tumor cells to chemotherapeutic agents and radiation but have not focused on delineating the contribution of PDK1 to pathway-specific mutations associated with various cancers other than the PI3K/AKT pathway. In this study, we show that the reduction of PDK1 by RNAi in melanoma and colon cancer cell lines activated in the MAPK pathway results in significant cell growth inhibition and apoptosis. Furthermore, PDK1 reduction in tumor cells resulted in impaired PAK kinase signaling, altered actin polymerization, and reduced cell migration. These studies show that PDK1 plays a pivotal role in MAPK and PI3K signaling in tumor cells. Mol Cancer Res; 8(3); 421-32. (C)2010 AACR.