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Cell Physiol Biochem. 2018;48(3):959-970. doi: 10.1159/000491964. Epub 2018 Jul 23.

Metformin Alleviates Radiation-Induced Skin Fibrosis via the Downregulation of FOXO3.

Author information

1
Department of Radiation Oncology, Yonsei University Health System, Seoul, Republic of Korea.
2
Department of Dermatology, Yonsei University Health System, Seoul, Seoul, Republic of Korea.
3
Radiation Epidemiology Team, Radiation Health Institute KHNP, Seongnam-si, Republic of Korea.
4
Department of Plastic Surgery, Yonsei University Health System, Seoul, Republic of Korea.
5
Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of Korea.

Abstract

BACKGROUND/AIMS:

Radiation-induced skin fibrosis is a common side effect of clinical radiotherapy. Our previous next-generation sequencing (NGS) study demonstrated the reduced expression of the regulatory α subunit of phosphatidylinositol 3-kinase (PIK3r1) in irradiated murine skin. Metformin has been reported to target the PIK3-FOXO3 pathway. In this study, we investigated the effects of metformin on radiation-induced skin fibrosis.

METHODS:

Metformin was orally administered to irradiated mice. Skin fibrosis was analyzed by staining with H&E and Masson's trichrome stain. The levels of cytokines and chemokines associated with fibrosis were analyzed by immunohistochemistry and quantitative RT-PCR. The roles of PIK3rl and FOXO3 in radiation-induced skin fibrosis were studied by overexpressing PIK3rl and transfecting FOXO3 siRNA in NIH3T3 cells and mouse-derived dermal fibroblasts (MDF).

RESULTS:

The oral administration of metformin significantly reduced radiation-induced skin thickening and collagen accumulation and significantly reduced the radiation-induced expression of FOXO3 in murine skin. Additionally, the overexpression of PIK3r1 reduced the radiation-induced expression of FOXO3, while FOXO3 silencing decreased the radiation-induced expression of TGFβ in vitro.

CONCLUSIONS:

The results indicated that metformin suppresses radiation-induced skin injuries by modulating the expression of FOXO3 through PIK3r1. Collectively, the data obtained in this study suggested that metformin could be a potent therapeutic agent for alleviating radiation-induced skin fibrosis.

KEYWORDS:

FOXO3; Metformin; PIK3r1; Radiation-induced skin fibrosis

PMID:
30036874
DOI:
10.1159/000491964
[Indexed for MEDLINE]
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