铜离子调控AKT信号通路及胃癌细胞增殖的机制研究

Based on current evidences, copper ion is essential for Ras-ERK signaling since it could promote the phosphorylation on ERK1/2 by MEK1. Due to constitutive and functional similarity between AKT and Ras-ERK signaling, we have creatively hypothesized that copper ion may critically influence AKT signaling by enhancing the activation of AKT, while reduced level of copper ion could significantly inactivate AKT and suppress the proliferation of gastric cancer cells. Results of our preliminary trials have possibly confirmed our hypothesis that the binding between copper ion and PDK1 could promote the phosphorylation on T308 of AKT1 by PDK1. Copper ion is the key to PDK1-AKT1 interaction and phosphorylation. In addition to the preliminary trials, we will utilize molecular-biological, cellular, human specimen and animal experiments to further study the mechanisms of copper ion on AKT signaling and proliferation of gastric cancer cells, especially the binding sites of copper ion. We believe that the completion of our project will not only provide theoretical basis for copper-inhibitory regimens against gastric cancer, but also offer a novel therapeutic option for all disorders featuring a pathological hyperactivation of AKT1 by PDK1.

现有文献证实，铜离子促进MEK1对ERK1/2的磷酸化，是Ras-ERK信号通路中的必要一环。鉴于AKT与Ras-ERK信号通路在组成和功能上有较高的相似性和重叠性，本研究创新性地提出如下猜想：铜离子增强AKT的活化水平，是AKT信号通路中的必要一环；抑制细胞内铜离子水平可以显著降低AKT活化程度，进而抑制胃癌细胞的增殖。预实验结果初步证实了研究猜想，即铜离子可能通过与PDK1的结合促进PDK1对AKT1的T308位点磷酸化激活；细胞内拥有足量的铜离子是PDK1活化AKT1的关键。本研究拟在预实验的基础上，运用分子生物学，细胞，人体标本及动物水平实验，进一步深入探讨铜离子调控AKT信号通路及胃癌细胞增殖的具体机制，寻找铜离子作用的具体靶点。我们相信，项目的完成不但会为铜抑制疗法在胃癌中的应用提供理论依据，而且对所有以PDK1介导的AKT1异常活化为基础的疾病都将提供新的治疗选择。

现有文献证实，铜离子促进MEK1对ERK1/2的磷酸化，是Ras-ERK信号通路中的必要一环。鉴于AKT与Ras-ERK信号通路在组成和功能上有较高的相似性和重叠性，本研究创新性地提出如下猜想：铜离子增强AKT的活化水平，是AKT信号通路中的必要一环；抑制细胞内铜离子水平可以显著降低AKT活化程度，进而抑制胃癌细胞的增殖。本研究的主要研究内容分为两部分：1. 铜离子调控AKT信号通路的机制；2. AKT信号通路在铜离子调控胃癌细胞增殖中的作用。通过分子生物学，细胞学，动物学及人体标本实验，本研究创新性地证实了：1. 铜离子通过与PDK1的直接结合促进PDK1对AKT1的T308位点磷酸化激活；细胞内拥有足量的铜离子是PDK1活化AKT1的关键；2. PDK1结合位点的突变将会显著下调铜离子介导胃癌细胞增殖效应。因此，本研究的科学意义不单在于为铜抑制疗法在胃癌中的应用提供理论依据，而且对所有以PDK1介导的AKT1异常活化为基础的疾病都将提供新的治疗选择。