WX20120108,a novel IAP antagonist,induces tumor cell autophagy via activating ROS-FOXO pathway  

作　　者：Rui Ding Xin Wang Wei Chen Zhi Li Ai-li Wei Qing-bin Wang Ai-hua Nie Li-li Wang 

机构地区：[1]Beijing Institute of Pharmacology and Toxicology,State Key Laboratory of Toxicology and Medical Countermeasures,Beijing 100850,China [2]State Key Laboratory of Functions and Applications of Medicinal Plants,Guizhou Medical University,Guiyang 550014,China

出　　处：《Acta Pharmacologica Sinica》2019年第11期1466-1479,共14页中国药理学报（英文版）

基　　金：the National Natural Science Foundation of China(Grant nos.81803567 and 81773790);the National Science and Technology Major Project of the Ministry of Science and Technology of China(Grant nos.2012ZX09301-001 and 2012ZX09301-003);partially supported by a project of the State Key Laboratory of Functions and Applications of Medicinal Plants,Guizhou Medical University(FAMP201708K).

摘　　要：Recently,inhibitor of apoptosis proteins(IAPs)and some IAP antagonists were found to regulate autophagy,but the underlying mechanisms remain unclear.WX20120108 is an analogue of GDC-0152(a known IAP antagonist)and displays more potent anti-tumor and autophagy-regulating activity in tumor cells,we investigated the regulatory mechanisms underlying WX20120108-induced autophagy.Using molecular docking and fluorescence polarization anisotropy(FPA)competitive assay,we first demonstrated that WX20120108,acting as an IAP antagonist,bound to the XIAP-BIR3,XIAP BIR2-BIR3,cIAP1 BIR3,and cIAP2 BIR3 domains with high affinities.In six cancer cell lines,WX20120108 inhibited the cell proliferation with potencies two to ten-fold higher than that of GDC-0152.In HeLa and MDA-MB-231 cells,WX20120108 induced caspase-dependent apoptosis and activated TNFα-dependent extrinsic apoptosis.On the other hand,WX20120108 induced autophagy in HeLa and MDA-MB-231 cells in dose-and time-dependent manners.We revealed that WX20120108 selectively activated Foxo3,evidenced by Foxo3 nuclear translocation in both gene modified cell line and HeLa cells,as well as the upregulated expression of Foxo3-targeted genes(Bnip3,Pik3c3,Atg5,and Atg4b),which played a key role in autophagy initiation.WX20120108-induced autophagy was significantly suppressed when Foxo3 gene was silenced.WX20120108 dose-dependently increased the generation of reactive oxygen species(ROS)in HeLa cells,and WX20120108-induced Foxo3 activation was completely blocked in the presence of catalase,a known ROS scavenger.However,WX20120108-induced ROS generation was not affected by cIAP1/2 or XIAP gene silencing.In conclusion,WX20120108-induced autophagy relies on activating ROS-Foxo3 pathway,which is independent of IAPs.This finding provides a new insight into the mechanism of IAP antagonist-mediated regulation of autophagy.

关 键 词：IAP ANTAGONISTS GDC-0152 WX20120108 apoptosis AUTOPHAGY carcinoma cells Foxo3 ROS CATALASE 

分 类 号：R73[医药卫生—肿瘤]