期刊
BIOCHEMICAL PHARMACOLOGY
卷 213, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2023.115592
关键词
Ferroptosis; SIRT3; Breast cancer; Tumor metastasis; Autophagy
This study found that SIRT3 regulates autophagy by phosphorylation of AMPK, and promotes ferroptosis by inducing the formation of BECN1-SLC7A11 complexes. This discovery has potential therapeutic value for treating breast cancer.
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-& beta;1 decreased the expression of epithelial-mesenchymal transition-related markers and inhibited the invasion and metastasis of breast cancer. Furthermore, TGF-& beta;1 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-& beta;1, suggesting that combination treatment of erastin and TGF-& beta;1 mediated autophagy by the SIRT3/AMPK signaling pathway. In addition, erastin-induced BECN1-SLC7A11 complexes were more abundant after co-treatment with TGF-& beta;1. This effect was inhibited by the autophagy inhibitor 3-methyladenine or siSIRT3, further revealing that combination treatment of erastin and TGF-& beta;1 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 SIRT3mediated 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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