Integrin β1-Mediated Cell⁻Cell Adhesion Augments Metformin-Induced Anoikis

Cell⁻cell adhesion plays an important role in regulation of cell proliferation, migration, survival, and drug sensitivity. Metformin, a first line drug for type 2 diabetes, has been shown to possess anti-cancer activities. However, whether cell⁻cell adhesion affects metformin anti-cancer activity is unknown. In this study, Microscopic and FACS analyses showed that metformin induced cancer cell⁻cell adhesion exemplified by cell aggregation and anoikis under glucose restriction. Furthermore, western blot and QPCR analyses revealed that metformin dramatically upregulated integrin β1 expression. Silencing of integrin β1 significantly disrupted cell aggregation and reduced anoikis induced by metformin. Moreover, we showed that p53 family member ΔNp63α transcriptionally suppressed integrin β1 expression and is responsible for metformin-mediated upregulation of integrin β1. In summary, this study reveals a novel mechanism for metformin anticancer activity and demonstrates that cell⁻cell adhesion mediated by integrin β1 plays a critical role in metformin-induced anoikis.