O-GlcNAcylation mediates H_(2)O_(2)-induced apoptosis through regulation of STAT3 and FOXO1  

作　　者：Chen-chun Zhang Yuan Li Chang-you Jiangv Qiu-min Lev Xing Liu Lan Ma Fei-fei Wang 

机构地区：[1]School of Basic Medical Sciences,State Key Laboratory of Medical Neurobiology,MOE Frontiers Center for Brain Science,Institutes of Brain Science,Department of Neurology,Pharmacology Research Center,Huashan Hospital,Fudan University,Shanghai,200032,China [2]Research Unit of Addiction Memory,Chinese Academy of Medical Sciences(2021RU009),Shanghai,200032,China

出　　处：《Acta Pharmacologica Sinica》2024年第4期714-727,共14页中国药理学报（英文版）

基　　金：supported by grants from the National Natural Science Foundation of China(32222033 to FFW,32330041 and 31930046 to LM,32271064 to CYJ,32270660 to QML,32171041 to XL);the Science Technology Innovation 2030 Project of China(2021ZD0203500 to FFW and LM,2021ZD0202104 to XL,2022ZD0214500 to CYJ);the CAMS Innovation Fund for Medical Sciences(2021-I2M-5-009 to LM and XL).

摘　　要：The O-linked-β-N-acetylglucosamine (O-GlcNAc) glycosylation (O-GlcNAcylation) is a critical post-translational modification that couples the external stimuli to intracellular signal transduction networks. However, the critical protein targets of O-GlcNAcylation in oxidative stress-induced apoptosis remain to be elucidated. Here, we show that treatment with H_(2)O_(2) inhibited O-GlcNAcylation, impaired cell viability, increased the cleaved caspase 3 and accelerated apoptosis of neuroblastoma N2a cells. The O-GlcNAc transferase (OGT) inhibitor OSMI-1 or the O-GlcNAcase (OGA) inhibitor Thiamet-G enhanced or inhibited H_(2)O_(2)-induced apoptosis, respectively. The total and phosphorylated protein levels, as well as the promoter activities of signal transducer and activator of transcription factor 3 (STAT3) and Forkhead box protein O 1 (FOXO1) were suppressed by OSMI-1. In contrast, overexpressing OGT or treating with Thiamet-G increased the total protein levels of STAT3 and FOXO1. Overexpression of STAT3 or FOXO1 abolished OSMI-1-induced apoptosis. Whereas the anti-apoptotic effect of OGT and Thiamet-G in H_(2)O_(2)-treated cells was abolished by either downregulating the expression or activity of endogenous STAT3 or FOXO1. These results suggest that STAT3 or FOXO1 are the potential targets of O-GlcNAcylation involved in the H_(2)O_(2)-induced apoptosis of N2a cells.

关 键 词：O-GLCNACYLATION oxidative stress APOPTOSIS STAT3 FOXO1 

分 类 号：R969[医药卫生—药理学]