Metformin Induces Non-small Cell Lung Cancer Cells Apoptosis Depending on AMPK-mediated RIP1 Downregulation
10.13865/j.cnki.cjbmb.2025.02.1363
- VernacularTitle:二甲双胍通过AMPK激酶下调受体相互作用蛋白1表达促进非小细胞肺癌细胞凋亡
- Author:
Min LI
1
;
Shao-Qing SHI
;
Yuan-Yuan ZHENG
Author Information
1. 昆明医科大学第一附属医院呼吸与危重症医学科,昆明 650032
- Publication Type:Journal Article
- Keywords:
lung cancer;
metformin;
receptor-interacting protein 1(RIP1);
heatshockprotein70(Hsp70);
AMP-activated protein kinas(AMPK)
- From:
Chinese Journal of Biochemistry and Molecular Biology
2025;41(4):551-559
- CountryChina
- Language:Chinese
-
Abstract:
The incidence and mortality rate of lung cancer rank among the highest worldwide,severely endangering human health and life.Metformin,an anti-diabetes drug,has been shown to elicit antican-cer activities in various tumors.However,its underlying mechanisms remain elusive.In this work,we explore the role of receptor-interacting protein 1(RIP 1)which plays a crucial role in the process of cell death,in metformin-induced anticancer activities in lung cancer.Metformin inhibits lung cancer cell pro-liferation in a dose-dependent manner and promotes apoptotic cell death,as evidenced by metformin-in-duced PARP and caspase cleavage.Furthermore,the pan-caspase inhibitor z-VAD-fmk reverses met-formin-induced cell death.Western blot and qPCR results suggest that metformin markedly downregulates RIP1 expression without affecting its mRNA and ubiquitination levels(0 vs 80 mmol/L,100％vs 20％,100％vs 15％).Additionally,co-immunoprecipitation and immunofluorescence results reveal that met-formin may suppress RIP1 expression in an Hsp70-dependent manner,as metformin promotes Hsp70 deg-radation,and Hsp70 endogenously interacts with RIP1.Subsequent CCK-8,flow cytometry,and West-ern blot analyses suggest that metformin decreases Hsp70/RIP1 expression through AMPK/PKA/GSK-3βaxis.Consistently,results from a subcutaneous transplant tumor model indicate that metformin retards tumor growth without affecting mouse body weight.Collectively,these data highlight the part of RIP1 in metformin-induced anticancer activities in lung cancer in vitro and in vivo,providing novel strategy for lung cancer administration.
