Department of Orthopedics, Huzhou Central Hospital, Huzhou, Zhejiang, 313000, China; Zhejiang University Huzhou Hospital, Huzhou, Zhejiang, 313000, China.
Central Laboratory, The First Affiliated Hospital of Huzhou University, Huzhou, Zhejiang, 313000, China; Huzhou Key Laboratory of Translational Medicine, The First Affiliated Hospital of Huzhou University, Huzhou, Zhejiang, 313000, China.
Eur J Pharmacol. 2023 Oct 15;957:176009. doi: 10.1016/j.ejphar.2023.176009. Epub 2023 Aug 22.
Osteosarcoma (OS) is a highly fatal bone tumor characterized by high degree of malignancy and early lung metastasis. Traditional chemotherapy fails in improving the efficacy and survival rate of patients with OS. Butyrate (NaBu) has been reported as a new antitumor drug for inhibiting proliferation and inducing apoptosis in various cancer cells. However, the effect of NaBu on the ferroptosis of OS is still unknown. This study aimed to investigate whether NaBu promotes erastin-induced ferroptosis in OS cells and to uncover the underlying mechanism. Here, we found that NaBu significantly enhanced erastin-induced ferroptosis in vitro and in vivo. Compared with the group that erastin used alonely, pre-treating with NaBu exacerbated erastin-meditated GSH depletion, lipid peroxidation, and mitochondrial morphologic changes in OS cells. In a subcutaneous OS model, NaBu combined with erastin significantly reduced tumor growth and increased the levels of 4-HNE. Mechanistically, NaBu downregulated SLC7A11 transcription via regulating ATF3 expression. Overexpression of ATF3 facilitated erastin to induce ferroptosis, while ATF3 knockdown attenuated NaBu-induced ferroptosis sensitivity. In conclusion, our findings revealed a previously unidentified role of NaBu in erastin-induced ferroptosis by regulating SLC7A11, suggesting that NaBu may be a potential therapeutic agent for OS treatment.
骨肉瘤（OS）是一种高度致命的骨肿瘤，其特点是恶性程度高，早期发生肺转移。传统化疗未能提高 OS 患者的疗效和生存率。丁酸钠（NaBu）已被报道为一种新型抗肿瘤药物，可抑制多种癌细胞的增殖并诱导其凋亡。然而，NaBu 对 OS 细胞铁死亡的影响尚不清楚。本研究旨在探讨 NaBu 是否促进 OS 细胞中铁死亡的发生，并揭示其潜在机制。本研究发现，NaBu 可显著增强 OS 细胞体外和体内的 erastin 诱导的铁死亡。与单独使用 erastin 的组相比，NaBu 预处理加剧了 OS 细胞中 GSH 耗竭、脂质过氧化和线粒体形态变化。在皮下 OS 模型中，NaBu 联合 erastin 可显著抑制肿瘤生长并增加 4-HNE 水平。机制上，NaBu 通过调节 ATF3 表达来下调 SLC7A11 的转录。过表达 ATF3 促进了 erastin 诱导的铁死亡，而 ATF3 敲低则减弱了 NaBu 诱导的铁死亡敏感性。总之，本研究结果揭示了 NaBu 通过调节 SLC7A11 在 erastin 诱导的铁死亡中的作用，提示 NaBu 可能是治疗 OS 的潜在治疗药物。
