铁死亡可以通过抑制抗氧化酶 GPX4 或系统 Xc 来诱导-,细胞内铁浓度增加,脂质过氧化。最近,有人提出铁死亡可能是诱导癌细胞死亡的有效方法,尽管铁死亡的具体相关性和机制尚未完全阐明。在这里,我们研究了铁死亡诱导剂 erastin 和 RSL3 对非小细胞肺癌 (NSCLC) 细胞的抗癌作用。RSL3 在 NSCLC 细胞中比 erastin 更有效地诱导细胞死亡,在 BEAS-2B 正常支气管上皮细胞中具有有限的细胞毒性。NSCLC 细胞对 RSL3 诱导死亡的敏感性取决于 GPX4 表达水平;RSL3 的作用可被 ferrostatin-1(一种铁死亡抑制剂)逆转,但不能被 Z-VAD-FMK、氯喹、巴弗洛霉素 A1 或 necrostatin-1 逆转。RSL3通过促进脂质过氧化诱导铁死亡,提高细胞内 LIP 浓度和 ROS 水平,并通过抑制 GPX4 和诱导 Nrf2/HO1 来阻断 GSH 向 GSSH 的转化。此外,RSL3 诱导自噬体但破坏自噬溶酶体的形成,溶酶体膜不稳定。GPX4 敲低对铁死亡表型的影响与 RSL3 相似。总之,RSL3 诱导的铁死亡取决于 NSCLC 细胞中 GPX4-Nrf2/HO1 的调节。这些结果可能有助于预测非小细胞肺癌和耐药癌细胞的铁死亡反应。GPX4 敲低对铁死亡表型的影响与 RSL3 相似。总之,RSL3 诱导的铁死亡取决于 NSCLC 细胞中 GPX4-Nrf2/HO1 的调节。这些结果可能有助于预测非小细胞肺癌和耐药癌细胞的铁死亡反应。GPX4 敲低对铁死亡表型的影响与 RSL3 相似。总之,RSL3 诱导的铁死亡取决于 NSCLC 细胞中 GPX4-Nrf2/HO1 的调节。这些结果可能有助于预测非小细胞肺癌和耐药癌细胞的铁死亡反应。
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GPX4 overexpressed non-small cell lung cancer cells are sensitive to RSL3-induced ferroptosis
Ferroptosis can be induced by inhibiting antioxidant enzymes GPX4 or system Xc−, increased intracellular iron concentrations, and lipid peroxidation. Recently, it has been suggested that ferroptosis can be an effective way to induce cancer cell death, although the specific relevance and mechanism of ferroptosis have not been fully elucidated. Here, we investigated the anticancer effects of ferroptosis inducers erastin and RSL3 on non-small cell lung cancer (NSCLC) cells. RSL3 induced cell death more effectively in NSCLC cells than erastin, with limited cytotoxicity in BEAS-2B normal bronchial epithelial cells. The sensitivity of NSCLC cells to RSL3 induced death was dependent on GPX4 expression levels; the effect of RSL3 was reversed by ferrostatin-1 (a ferroptosis inhibitor) but not by Z-VAD-FMK, chloroquine, bafilomycin A1, or necrostatin-1. RSL3 induced ferroptosis by promoting lipid peroxidation, elevating intracellular LIP concentration and ROS level, and blocking GSH-to-GSSH conversion through the inhibition of GPX4 and induction of Nrf2/HO1. Furthermore, RSL3 induced autophagosomes but disrupted the formation of autolysosomes with lysosomal membrane destabilization. GPX4 knockdown had a similar effect on ferroptosis phenotypes as RSL3. Taken together, RSL3-induced ferroptosis depends on the regulation of GPX4-Nrf2/HO1 in NSCLC cells. These results may be useful in predicting the ferroptosis response in NSCLC as well as drug resistant cancer cells.