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  • Phenformin Down-Regulates c-Myc Expression to Suppress the Expression of Pro-Inflammatory Cytokines in Keratinocytes.

Phenformin Down-Regulates c-Myc Expression to Suppress the Expression of Pro-Inflammatory Cytokines in Keratinocytes.

Cells (2022-08-13)
Guanyi Liu, Dingyang Li, Liwei Zhang, Qiuping Xu, Dexuan Zhuang, Panpan Liu, Ling Hu, Huiting Deng, Jianfeng Sun, Shuangshuang Wang, Bin Zheng, Jing Guo, Xunwei Wu
ABSTRACT

The treatment of many skin inflammation diseases, such as psoriasis and atopic dermatitis, is still a challenge and inflammation plays important roles in multiple stages of skin tumor development, including initiation, promotion and metastasis. Phenformin, a biguanide drug, has been shown to play a more efficient anti-tumor function than another well-known biguanide drug, metformin, which has been reported to control the expression of pro-inflammatory cytokines; however, little is known about the effects of phenformin on skin inflammation. This study used a mouse acute inflammation model, ex vivo skin organ cultures and in vitro human primary keratinocyte cultures to demonstrate that phenformin can suppress acute skin inflammatory responses induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in vivo and significantly suppresses the pro-inflammatory cytokines IL-1β, IL-6 and IL-8 in human primary keratinocytes in vitro. The suppression of pro-inflammatory cytokine expression by phenformin was not directly through regulation of the MAPK or NF-κB pathways, but by controlling the expression of c-Myc in human keratinocytes. We demonstrated that the overexpression of c-Myc can induce pro-inflammatory cytokine expression and counteract the suppressive effect of phenformin on cytokine expression in keratinocytes. In contrast, the down-regulation of c-Myc produces effects similar to phenformin, both in cytokine expression by keratinocytes in vitro and in skin inflammation in vivo. Finally, we showed that phenformin, as an AMPK activator, down-regulates the expression of c-Myc through regulation of the AMPK/mTOR pathways. In summary, phenformin inhibits the expression of pro-inflammatory cytokines in keratinocytes through the down-regulation of c-Myc expression to play an anti-inflammation function in the skin.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Phorbol 12-myristate 13-acetate, ≥99% (TLC), film or powder
Supelco
Phenformin hydrochloride, analytical standard
Sigma-Aldrich
Phenformin hydrochloride, ≥98% (HPLC)