项目名称: IAP抑制剂GDC-0152通过自噬促进急性髓细胞白血病细胞凋亡的机制研究
项目编号: No.81500135
项目类型: 青年科学基金项目
立项/批准年度: 2016
项目学科: 医药、卫生
项目作者: 胡荣
作者单位: 中国医科大学
项目金额: 18万元
中文摘要: 自噬对AML细胞具有促进和抑制凋亡的双重作用。我们的研究发现IAP抑制剂GDC-0152可以通过自噬促进AML细胞(HL-60、KG1及THP-1)凋亡,抑制HL-60细胞p62、Beclin 1、Bcl-2和Akt表达,促进Bax表达。结合相关理论,我们推测GDC-0152可能在抑制IAP后减少了AML细胞p62的降解,使p62引导融合蛋白或抗凋亡蛋白至自噬体被降解进而促进凋亡。在促进p62引导泛素化蛋白至自噬体的同时,GDC-0152还可能通过调节Beclin 1/Bcl-2复合体和Beclin 1-Vps34复合体增加自噬体形成进而促进AML细胞凋亡。上述过程均可能受到ROS和相关信号通路的调节。因此,我们拟通过对p62、Beclin 1以及ROS和相关信号通路三个方面的研究明确GDC-0152通过自噬促进AML细胞凋亡的相关机制。本研究的完成将为IAP抑制剂治疗AML提供理论依据。
中文关键词: IAP抑制剂;自噬;凋亡;急性髓细胞白血病
英文摘要: Autophagy in acute myelogenous leukemia (AML) cells plays a dual role in promoting and inhibiting apoptosis. Our study found that IAP inhibitor GDC-0152 could promote apoptosis of AML cells(HL-60、KG1 and THP-1) through autophagy with down-regulation of p62, Beclin1, Bcl-2 and Akt expression, and upregulation of Bax expression in HL-60 cells. Combined with the related theories, we speculated that GDC-0152 might reduce p62 degradation by ubiquitination in AML cells after inhibition of IAP and make p62 lead ubiquitinated fusion proteins or antiapoptotic proteins to autophagosome and then promote AML cells apoptosis. While promoting p62 to guide the ubiquitinated protein to autophagosome, GDC-0152 may also adjust Beclin 1/ Bcl-2 complex and Beclin 1-Vps34 complex, and then increase autophagy and promote apoptosis of AML cells. The above process may be ROS-dependent and involve the related signaling pathways. On this basis, we prepare to study the mechanism of how IAP inhibitor GDC- 0152 promotes apoptosis of AML cells through autophagy from the following aspects: the p62,Beclin 1 and ROS related signal pathways. The completion of this study will provide theoretical basis for IAP inhibitors in the treatment of AML.
英文关键词: IAP inhibitor;autophagy;apoptosis;acute myelogenous leukemia