MT1DP loaded by folate-modified liposomes sensitizes erastin-induced ferroptosis via regulating miR-365a-3p/NRF2 axis in non-small cell lung cancer cells
MT1DP loaded by folate-modified liposomes sensitizes erastin-induced ferroptosis via regulating miR-365a-3p/NRF2 axis in non-small cell lung cancer cells
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DOI：
10.1038/s41419-020-02939-3
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发表时间：
2020-09-14
影响因子：
9
通讯作者：
Li, Wentong
中科院分区：
文献类型：
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作者：
Gai, Chengcheng;Liu, Chuanliang;Li, Wentong
虽然铁凋亡已被认为是一种新的抗肿瘤治疗，核因子红细胞2相关因子2（NRF 2）的高表达已被报道是一种抗氧化转录因子，保护恶性细胞从铁凋亡。金属硫蛋白1D假基因（MT 1DP）是一种长链非编码RNA（lncRNA），它通过抑制抗氧化作用而加重氧化应激。本研究旨在探讨MT 1DP是否能调节erastin诱导的非小细胞肺癌（NSCLC）细胞铁凋亡，并阐明其作用机制。我们发现，异位表达MT 1DP敏感A549和H1299细胞erastin诱导的铁凋亡通过下调NRF 2;此外，异位MT 1DP上调丙二醛（MDA）和活性氧（ROS）水平，增加细胞内亚铁离子浓度，并减少谷胱甘肽（GSH）水平暴露于erastin的癌细胞，而下调MT 1DP显示相反的效果。RNA pulldown实验和双荧光素酶报告基因实验证实MT 1DP通过稳定miR-365 a-3 p来调控NRF 2的表达。由于erastin的低溶解度限制了其有效应用，我们进一步制备了叶酸（FA）修饰的脂质体（FA-LP）纳米粒，用于靶向共递送erastin和MT 1DP，以提高药物/基因组合的生物利用度和效率。Erastin/MT 1DP @ FA-LP（E/M@FA-LP）使Erastin诱导的铁凋亡敏化，细胞GSH水平降低，脂质ROS升高。体内实验表明，E/M@FA-LPs对肺癌移植瘤有良好的治疗作用。简而言之，我们的研究结果确定了一种新的策略，通过MT 1DP/miR-365 a-3 p/NRF 2轴来提高非小细胞肺癌中erastin诱导的铁凋亡。
Although ferroptosis has been recognized as a novel antitumoral treatment, high expression of nuclear factor erythroid 2-related factor 2 (NRF2) has been reported to be an antioxidant transcript factor that protects malignant cells from ferroptosis. Previous findings indicated that metallothionein 1D pseudogene (MT1DP), a long noncoding RNA (lncRNA), functioned to aggravate oxidative stress by repressing antioxidation. Here we aimed at assessing whether MT1DP could regulate erastin-induced ferroptosis on non-small cell lung cancer (NSCLC) and elucidating the mechanism. We found that ectopic expression of MT1DP sensitized A549 and H1299 cells to erastin-induced ferroptosis through downregulation of NRF2; in addition, ectopic MT1DP upregulated malondialdehyde (MDA) and reactive oxygen species (ROS) levels, increased intracellular ferrous iron concentration, and reduced glutathione (GSH) levels in cancer cells exposed to erastin, whereas downregulation of MT1DP showed the opposite effect. RNA pulldown assay and dual-luciferase reporter assay confirmed that MT1DP modulated the expression of NRF2 via stabilizing miR-365a-3p. As low solubility of erastin limits its efficient application, we further prepared folate (FA)-modified liposome (FA-LP) nanoparticles for targeted co-delivery of erastin and MT1DP to enhance the bioavailability and the efficiency of the drug/gene combination. Erastin/MT1DP@FA-LPs (E/M@FA-LPs) sensitized erastin-induced ferroptosis with decreased cellular GSH levels and elevated lipid ROS. In vivo analysis showed that E/M@FA-LPs had a favorable therapeutic effect on lung cancer xenografts. In short, our findings identify a novel strategy to elevate erastin-induced ferroptosis in NSCLCs acting through the MT1DP/miR-365a-3p/NRF2 axis.