Phenformin Promotes Keratinocyte Differentiation via the Calcineurin/NFAT Pathway.
Details
Serval ID
serval:BIB_B79643FFD3B7
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Phenformin Promotes Keratinocyte Differentiation via the Calcineurin/NFAT Pathway.
Journal
The Journal of investigative dermatology
ISSN
1523-1747 (Electronic)
ISSN-L
0022-202X
Publication state
Published
Issued date
01/2021
Peer-reviewed
Oui
Volume
141
Number
1
Pages
152-163
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Abstract
Phenformin is a drug in the biguanide class that was previously used to treat type 2 diabetes. We have reported the antitumor activities of phenformin to enhance the efficacy of BRAF-MAPK kinase-extracellular signal-regulated kinase 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 7,12-dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol-13-acetate 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. Pharmacologic or genetic inhibition of calcineurin and NFAT signaling reverses the effects of phenformin on keratinocyte differentiation. Taken together, our study reveals an antitumor activity of phenformin to promote keratinocyte differentiation that warrants future translational efforts to repurpose phenformin for the treatment of cutaneous squamous cell carcinomas.
Keywords
Animals, Calcineurin/metabolism, Cell Differentiation, Humans, Hypoglycemic Agents/pharmacology, Keratinocytes/drug effects, Keratinocytes/metabolism, Keratinocytes/pathology, Melanoma/drug therapy, Melanoma/metabolism, Melanoma/pathology, Mice, Neoplasms, Experimental, Nitrofurans/metabolism, Phenformin/pharmacology, Signal Transduction, Skin/metabolism, Skin/pathology, Skin Neoplasms/drug therapy, Skin Neoplasms/metabolism, Skin Neoplasms/pathology
Pubmed
Web of science
Open Access
Yes
Create date
08/07/2020 11:55
Last modification date
02/12/2023 7:16