Abstract
Phenformin is a drug in the biguanide classify that was previously used to treat type 2 diabetes. We have reported the anti-tumor activities of phenformin to enhance the efficacy of BRAF-MEK-ERK pathway inhibition and to inhibit myeloid-derived suppressor cells in various melanoma models. Here we demonstrate that phenformin suppresses tumor growth and promotes keratinocyte differentiation in the DMBA/TPA two stage skin carcinogenesis mouse model. Moreover, phenformin enhances the suspension-induced differentiation of mouse and human keratinocytes. Mechanistically, phenformin induces the nuclear translocation of NFATc1 in keratinocytes in an AMPK-dependent manner. Pharmacological or genetic inhibition of calcineurin/NFAT signaling reverses the effects of phenformin on keratinocyte differentiation. Taken together, our study reveals an anti-tumor activity of phenformin to promote keratinocyte differentiation that warrants future translational efforts to repurpose phenformin for the treatment of cutaneous squamous cell carcinomas.
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