多发性骨髓瘤细胞基于Caspase-3/AA/Akt信号通路启动抗凋亡效应及机制研究

项目名称： 多发性骨髓瘤细胞基于Caspase-3/AA/Akt信号通路启动抗凋亡效应及机制研究

项目编号： No.81201668

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 肿瘤学1

项目作者： 阳泰

作者单位： 成都医学院

项目金额： 23万元

中文摘要： 研究多发性骨髓瘤（MM）细胞凋亡后抗凋亡效应启动的策略和机制是洞察其为何难以消灭、容易复发的重要渠道。我们发现，药物诱导MM细胞凋亡后会增强IL-10的表达促其增殖和存活。综合前期研结果和文献报道，我们推测MM细胞凋亡后，capase-3可诱导花生四烯酸（AA）产生进而活化Akt增强细胞因子分泌，使MM细胞加速增殖应对药物攻击。为证实这一科学假说，我们拟采用抗体芯片和PCRarray 研究MM细胞凋亡后，细胞因子以及抗凋亡基因表达谱；进一步利用小分子阻断以及RNAi探明细胞凋亡前后caspase-3、AA、Akt等与细胞因子表达相互关系；最后，由于MM细胞凋亡后抗凋亡效应最终由Akt活化介导细胞因子分泌、加速其增殖实现。所以 IL-6单抗、Akt及NF-κB抑制剂在MM治疗中非常重要，研究IL-6单抗以及Akt、NF-κB抑制剂协同抗MM效应，可为MM治疗的药物策略和组合提供重要理论依据。

中文关键词： 多发性骨髓瘤；凋亡；协同；机制；小分子

英文摘要： Research on the strategies and mechanisms of anti-apoptotic effects induced by the apoptosis of multiple myeloma (MM) is the insight into why MM is difficult to cure. Our preliminary work showed treatment of multiple myeloma cells with doxorubicin, camptothecin and JAK inhibitor resulted in a substantial increase in the production of cytokines such as IL-10. The increase of cytokines could provide proliferative and anti-apoptotic signals helping tumor cells to escape drug mediated destruction. From our preliminary work and the relative background knowledge, the mechanism was deduced as follows: in the apoptotic process of myeloma cells, Caspase-3, a key executioner of apoptosis, activates iPLA2 to stimulate the production of arachidonic acid, and then the arachidonic acid could enhance activity of NF-κB by Akt activation. Finally, the enhance activity of NF-κB results in the elevated production of cytokines, thereby promoting tumor cell proliferation and survival. Based on the above theory, this study was carried out as follows: First, the expression level of cytokine and apoptotic gene induced by apoptosis was analyzed by human cytokine antibody array and PCR array respectively. Second, the relationship between cytokines and caspase-3 or iPLA was analyzed by small molecule blocker and RNAi. Finally, as importan

英文关键词： multiple myeloma;；apoptosis；synergy；mechanism；small molecule