Clinical Pharmacology Institute, Nanchang University, Nanchang 330031, People's Republic of China.
Department of Pathology, the First Affiliated Hospital of Nanchang University, Nanchang 330006, People's Republic of China.
Biochem Pharmacol. 2023 Jul;213:115592. doi: 10.1016/j.bcp.2023.115592. Epub 2023 May 16.
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.
铁死亡是一种与铁积累和脂质过氧化有关的自噬依赖性细胞死亡，它在抗癌活性中起着至关重要的作用。Sirtuin 3（SIRT3）通过磷酸化激活蛋白激酶（AMPK）正向调节自噬。然而，SIRT3 介导的自噬是否可以通过诱导 BECN1-SLC7A11 复合物的形成来抑制胱氨酸/谷氨酸反向转运体（system Xc）的活性，从而促进铁死亡的诱导尚不清楚。我们使用体外和体内模型揭示了用 erastin 和 TGF-β1 联合治疗可降低上皮-间充质转化相关标志物的表达，并抑制乳腺癌的侵袭和转移。此外，TGF-β1 促进 MCF-7 细胞和荷瘤裸鼠模型中 erastin 诱导的铁死亡相关指标。有趣的是，在 erastin 和 TGF-β1 联合处理后，SIRT3、p-AMPK 和自噬相关标志物的表达明显升高，表明 erastin 和 TGF-β1 的联合治疗通过 SIRT3/AMPK 信号通路介导自噬。此外，在与 TGF-β1 联合处理后，erastin 诱导的 BECN1-SLC7A11 复合物更加丰富。这种作用被自噬抑制剂 3-甲基腺嘌呤或 siSIRT3 抑制，进一步表明 erastin 和 TGF-β1 的联合治疗通过诱导 BECN1-SLC7A11 复合物的形成来介导自噬依赖性铁死亡。我们的结果与 BECN1 直接结合 SLC7A11 以抑制 system Xc 活性的概念一致。总之，我们的研究证实，SIRT3 介导的自噬通过诱导 BECN1-SLC7A11 复合物的形成有利于铁死亡介导的抗癌活性，这是治疗乳腺癌的一种潜在治疗方法。
