Literature citations

SIRT3-mediated autophagy contributes to ferroptosis-induced anticancer by inducing the formation of BECN1-SLC7A11 complex.

Ferroptosis is an autophagy-dependent cell death associated with iron accumulation and lipid peroxidation, which plays a crucial part in anticancer activity. Sirtuin 3 (SIRT3) positively regulates autophagy by phosphorylation of activated protein kinase (AMPK). However, whether SIRT3-mediated autophagy can inhibit the cystine/glutamate antiporter (system Xc-) activity by inducing the formation of a BECN1-SLC7A11 complex and consequently promote induction of ferroptosis is unknown. Using both in vitro and in vivo models, we revealed that combination treatment with erastin and TGF-β1 decreased the expression of epithelial-mesenchymal transition-related markers and inhibited the invasion and metastasis of breast cancer. Furthermore, TGF-β1 promoted erastin-induced ferroptosis-related indicators in MCF-7 cells and tumor-bearing nude mice models. Interestingly, the expression of SIRT3, p-AMPK, and autophagy- related markers were significantly elevated after co-treatment with erastin and TGF-β1, suggesting that combination treatment of erastin and TGF-β1 mediated autophagy by the SIRT3/AMPK signaling pathway. In addition, erastin-induced BECN1-SLC7A11 complexes were more abundant after co-treatment with TGF-β1. This effect was inhibited by the autophagy inhibitor 3-methyladenine or siSIRT3, further revealing that combination treatment of erastin and TGF-β1 mediated autophagy-dependent ferroptosis by inducing the formation of BECN1-SLC7A11 complexes. Our results agreed with the concept that BECN1 directly binds to SLC7A11 to inhibit system Xc- activity. In summary, our studies confirmed that SIRT3-mediated autophagy is conducive to ferroptosis-mediated anticancer activity by inducing the formation of BECN1-SLC7A11 complexes, which is a potential therapeutic approach for treating breast cancer.

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