Metformin Promotes HaCaT Cell Apoptosis through Generation of Reactive Oxygen Species via Raf-1-ERK1/2-Nrf2 Inactivation
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ORIGINAL ARTICLE
Metformin Promotes HaCaT Cell Apoptosis through Generation of Reactive Oxygen Species via Raf-1-ERK1/2-Nrf2 Inactivation Xiaoyan Wang,1,2 Ronghua Li,1 Xintong Zhao,1 Xiaojing Yu,1,3 and Qing Sun1,3
Although metformin (MET) may be useful for the treatment of psoriasis, the mechanisms underlying its method of action have yet to be fully elucidated. Here, the relationship between MET function and reactive oxygen species (ROS) levels and the underlying mechanism were explored in human immortalized keratinocyte cell line (HaCaT). HaCaT cells were incubated with MET at 0, 10, 20, 40, and 60 mM for 24 h. The cell viability was evaluated by the CCK-8 assay. The cell apoptosis rate and intracellular ROS levels were examined using flow cytometry. The protein expression and the phosphorylation levels of nuclear factor erythroid-derived 2 related factor 2 (Nrf2), Raf-1, and ERK1/2 were assessed by Western blot. The specific ROS scavenger N-acetyl-cysteine (NAC) and the specific Nrf2 agonist Oltipraz (OPZ) were used to analyze the effect of MET. MET decreased HaCaT cell proliferation and induced HaCaT cell apoptosis in a dose-dependent manner. MET was found to elevate intracellular ROS levels in a dose-dependent manner, while pretreatment with NAC attenuated these effects. MET inhibits the protein expression and the phosphorylation levels of Nrf2. The combination of OPZ and MET can significantly increase the cell viability, decrease the rate of apoptosis, and attenuate the intracellular ROS levels relative to MET alone. MET inhibits the protein expression and the phosphorylation levels of Raf-1 and ERK1/2. MET was found to attenuate Raf-1-ERK1/2 signaling in HaCaT cells to suppress the expression and phosphorylation levels of Nrf2, which contributed to the intracellular generation of ROS and the pro-apoptotic effects of MET. Abstract—
KEY WORDS: psoriasis; metformin; ROS; Raf-1; ERK; Nrf2.
INTRODUCTION Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10753-018-0749-z) contains supplementary material, which is available to authorized users. 1
Department of Dermatology, Qilu Hospital of Shandong University, Jinan, Shandong 250000, China 2 Department of Dermatology, Qingdao Municipal Hospital, Qingdao, Shandong 266000, China 3 To whom correspondence should be addressed at Department of Dermatology, Qilu Hospital of Shandong University, Jinan, Shandong 250000, China. E-mails: [email protected]; [email protected]
Psoriasis is a common, recurrent, chronic inflammatory skin disease affecting 3% of the general population and leads to significant morbidity. Psoriasis is characterized by the development of erythematous papules and overlying scaly plaques [1]. The etiology of psoriasis is complex and remains unclear. Although many therapeutic strategies have been developed for the treatment of psoriasis, many psoriasis patients still suffer from frequent relapse, adverse drug effects, and other unwanted reactions [2]. It is necessary to identify new therapies.
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