Department of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University, Jinan, China; Shandong Key Laboratory of Oral Tissue Regeneration, Jinan, China; Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China; Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, China.
Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
J Invest Dermatol. 2021 Jan;141(1):152-163. doi: 10.1016/j.jid.2020.05.114. Epub 2020 Jun 30.
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.
苯乙双胍是一种双胍类药物，曾用于治疗 2 型糖尿病。我们已经报道了苯乙双胍的抗肿瘤活性，以增强 BRAF-MAPK 激酶-细胞外信号调节激酶通路抑制和抑制各种黑色素瘤模型中的髓样来源抑制细胞的功效。在这里，我们证明苯乙双胍可抑制 7,12-二甲基苯并[a]蒽/12-O-十四烷酰佛波醇-13-醋酸酯两阶段皮肤致癌作用小鼠模型中的肿瘤生长并促进角质形成细胞分化。此外，苯乙双胍可增强小鼠和人角质形成细胞的悬浮诱导分化。从机制上讲，苯乙双胍以 AMPK 依赖性方式诱导角质形成细胞核内 NFATc1 的易位。钙调神经磷酸酶和 NFAT 信号转导的药理学或遗传抑制可逆转苯乙双胍对角质形成细胞分化的作用。综上所述，我们的研究揭示了苯乙双胍的抗肿瘤活性，可促进角质形成细胞分化，值得进一步开展转化研究，重新利用苯乙双胍治疗皮肤鳞状细胞癌。
