title: Metformin Promotes AMP-activated Protein Kinase-independent Suppression of ΔNp63α Protein Expression and Inhibits Cancer Cell Viability.
abstract: The blood glucose modifier metformin is used to treat type II diabetes and has also been shown to possess anticancer activities. Recent studies indicate that glucose deprivation can greatly enhance metformin-mediated inhibition of cell viability, but the molecular mechanism involved in this inhibition is unclear. In this study, we report that, under glucose deprivation, metformin inhibited expression of ΔNp63α, a p53 family member involved in cell adhesion pathways, resulting in disruption of cell matrix adhesion and subsequent apoptosis in human squamous carcinoma cells. We further show that metformin promoted ΔNp63α protein instability independent of AMP-activated protein kinase and that WWP1, an E3 ligase of ΔNp63α, was involved in metformin-mediated down-regulation of ΔNp63α levels. In addition, we demonstrate that a combination of metformin and the glycolysis inhibitor 2-deoxy-d-glucose significantly inhibited ΔNp63α expression and also suppressed xenographic tumor growthin vivoIn summary, this study reveals a new mechanism for metformin-mediated anticancer activity and suggests a new strategy for treating human squamous cell carcinoma.
authors.affiliation: From the Center of Growth, Metabolism, and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610064, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Yi
authors.affiliation: From the Center of Growth, Metabolism, and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610064, China.
authors.forename: Deshi
authors.initials: D
authors.lastname: Chen
authors.affiliation: From the Center of Growth, Metabolism, and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610064, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Ao
authors.affiliation: From the Center of Growth, Metabolism, and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610064, China.
authors.forename: Shengnan
authors.initials: S
authors.lastname: Sun
authors.affiliation: From the Center of Growth, Metabolism, and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610064, China.
authors.forename: Min
authors.initials: M
authors.lastname: Wu
authors.affiliation: From the Center of Growth, Metabolism, and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610064, China.
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Li
authors.affiliation: From the Center of Growth, Metabolism, and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610064, China.
authors.forename: Johann
authors.initials: J
authors.lastname: Bergholz
authors.affiliation: From the Center of Growth, Metabolism, and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610064, China.
authors.forename: Yujun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: From the Center of Growth, Metabolism, and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610064, China jimzx@scu.edu.cn.
authors.forename: Zhi-Xiong
authors.initials: ZX
authors.lastname: Xiao
mesh_terms: D055372:AMP-Activated Protein Kinases; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003847:Deoxyglucose / Q000494:pharmacology; D004359:Drug Therapy, Combination; D064593:Heterografts; D006801:Humans; D008687:Metformin / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D055550:Protein Stability / Q000187:drug effects; D014157:Transcription Factors / Q000037:antagonists & inhibitors*; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D008687:Metformin; D003847:Deoxyglucose; D055372:AMP-Activated Protein Kinases
keywords: 2-DG; AMP-activated kinase (AMPK); anoikis; apoptosis; cell adhesion; glucose; metformin; p63; squamous cell carcinoma