Metformin leads to accumulation of reactive oxygen species by inhibiting the NFE2L1 expression in human hepatocellular carcinoma cells

Shanshan Gou, Lu Qiu, Qiufang Yang, Peng Li, Xiaowen Zhou, Yixuan Sun, Xiuman Zhou, Wenshan Zhao, Wenjie Zhai, Guodong Li, Yahong Wu, Yonggang Ren, Yuanming Qi, Yiguo Zhang, Yanfeng Gao
Toxicology and Applied Pharmacology 2021 April 7, : 115523
Metformin, as the first-line drug for the treatment of type 2 diabetes mellitus, has been shown to possess a capability to activate or inhibit the production of reactive oxygen species (ROS) in different ways. However, the detailed mechanisms of the opposite effect are poorly understood. Here we provide evidence that metformin induces accumulation of ROS by inhibiting the expression of a core antioxidant transcription factor nuclear factor erythroid 2 like 1 (NFE2L1/Nrf1) in human hepatocellular carcinoma HepG2 cells. In the present study, we originally found that the increased ROS induced by metformin was blunted in NFE2L1 knockdown cell line. Furtherly by examining the effects of metformin on endogenous and exogenous NFE2L1, we also found metformin could not only inhibit the transcription of NFE2L1 gene, but also promote the degradation of NFE2L1 protein at the post-transcriptional level, whereas this effect can be reversed by high glucose. The inhibitory effect of metformin on NFE2L1 was investigated to occur through the N-terminal domain (NTD) of NFE2L1 protein, and its downregulation by metformin was in an AMP-activated protein kinase (AMPK)-independent manner. But the activation of AMPK signaling pathway by metformin in NFE2L1 knockdown HepG2 cells is reversed, indicating that NFE2L1 may be an important regulator of AMPK signal. Altogether, this work provides a better understanding of the relationship between metformin and oxidative stress, and hence contributes to translational study of metformin through its hypoglycemic and tumor suppressive effects.

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