Metformin induces Ferroptosis by inhibiting UFMylation of SLC7A11 in breast cancer

Abstract

Background Ferroptosis is a newly defined form of regulated cell death characterized by the iron-dependent accumulation of lipid peroxidation and is involved in various pathophysiological conditions, including cancer. Targeting ferroptosis is considered to be a novel anti-cancer strategy. The identification of FDA-approved drugs as ferroptosis inducers is proposed to be a new promising approach for cancer treatment. Despite a growing body of evidence indicating the potential efficacy of the anti-diabetic metformin as an anti-cancer agent, the exact mechanism underlying this efficacy has not yet been fully elucidated. Methods The UFMylation of SLC7A11 is detected by immunoprecipitation and the expression of UFM1 and SLC7A11 in tumor tissues was detected by immunohistochemical staining. The level of ferroptosis is determined by the level of free iron, total/lipid Ros and GSH in the cells and the morphological changes of mitochondria are observed by transmission electron microscope. The mechanism in vivo was verified by in situ implantation tumor model in nude mice. Results Metformin induces ferroptosis in an AMPK-independent manner to suppress tumor growth. Mechanistically, we demonstrate that metformin increases the intracellular Fe2+ and lipid ROS levels. Specifically, metformin reduces the protein stability of SLC7A11, which is a critical ferroptosis regulator, by inhibiting its UFMylation process. Furthermore, metformin combined with sulfasalazine, the system xc− inhibitor, can work in a synergistic manner to induce ferroptosis and inhibit the proliferation of breast cancer cells. Conclusions This study is the first to demonstrate that the ability of metformin to induce ferroptosis may be a novel mechanism underlying its anti-cancer effect. In addition, we identified SLC7A11 as a new UFMylation substrate and found that targeting the UFM1/SLC7A11 pathway could be a promising cancer treatment strategy.

SLC7A11 regulated by NRF2 modulates esophageal squamous cell carcinoma radiosensitivity by inhibiting ferroptosis

“…Mechanistically, in the present study, we revealed that the activation of NRF2 weakened radiation-induced ROS generation and lipid peroxidation, alleviating RT-induced ferroptosis and promoting radioresistance in ESCC. We additionally proposed that activated NRF2 could directly combine with the promoter region of SLC7A11 to regulate its transcription, which is related to the inhibition of ferroptosis [ 56 , 57 ].…”

BRAF-activated WT1 contributes to cancer growth and regulates autophagy and apoptosis in papillary thyroid carcinoma

“…Lysates of the IHH4 cells and BCPAP cells were added to SDS-PAGE sample loading buffer (Beyotime, Shanghai, China) and boiled at 100 °C for 8–10 min. Western blotting was conducted as previously described[ 24 , 25 ]. The following antibodies were showed in supported information, and anti-actin as an internal control.…”

Ferroptosis-mediated Crosstalk in the Tumor Microenvironment Implicated in Cancer Progression and Therapy

“…Starvation of cystine reduces the level GSH by directly decreasing synthesis and the GCN2-eIF2α-ATF4-CHAC1 pathway, thereby inducing ferroptosis in TNBC cells ( Chen et al, 2017 ). The anti-diabetic drug metformin reduces the stability of xCT by inhibiting its UFMylation, thus inducing ferroptosis and inhibiting the proliferation of breast cancer cells ( Yang et al, 2021 ). In contrast, MUC1-C, a transmembrane protein, can maintain the GSH level and redox balance by forming a complex with xCT and the CD44 variants (CD44v), which inhibits ferroptosis in breast cancer cells ( Ishimoto et al, 2011 ).…”