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MT1DP loaded by folate-modified liposomes sensitizes erastin-induced ferroptosis via regulating miR-365a-3p/NRF2 axis in non-small cell lung cancer cells.

ABSTRACT: 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.

SUBMITTER: Gai C

PROVIDER: S-EPMC7490417 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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MT1DP loaded by folate-modified liposomes sensitizes erastin-induced ferroptosis via regulating miR-365a-3p/NRF2 axis in non-small cell lung cancer cells.

Gai Chengcheng C Liu Chuanliang C Wu Xinghan X Yu Mengyu M Zheng Jie J Zhang Weifen W Lv Shijun S Li Wentong W

Cell death & disease 20200914 9

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 ferro ...[more]

PMID: 32929075

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Project description:BackgroundFerroptosis has been proven to contribute to the progression of myocardial ischemia/reperfusion (I/R) injury and can be inhibited or promoted by ATF3. Short-chain fatty acids (SCFAs) have shown benefits in various cardiovascular diseases with anti-inflammatory and antioxidant effects. However, the impact of SCFAs on ferroptosis in ischemic-stimulated cardiomyocytes remains unknown. This study aimed to investigate the effect of SCFAs on cardiomyocyte ferroptosis, the expression of ATF3, and its potential upstream regulators.Methods and resultsThe expression of ATF3, ferroptosis pathway geneset (FPG), and geneset of potential regulators for ATF3 (GPRA, predicted by the PROMO database) was explored in the public human myocardial infarction single-cell RNA-seq (sma) dataset. Cardiomyocyte data was extracted from the dataset and re-clustered to explore the FPG, ATF3, and GPRA expression patterns in cardiomyocyte subclusters. A dose-dependent toxic experiment was run to detect the suitable dose for SCFA treatment. The erastin-induced ferroptosis model and hypoxia-reoxygenation (H/R) model (10 h of hypoxia followed by 6 h of reoxygenation) were adopted to assess the effect of SCFAs via the CCK8 assay. Gene expression was examined via RT-PCR and western blot. Ferroptosis markers, including lipid peroxides and Fe2+, were detected using the liperfluo and ferroOrange probes, respectively. In the sma dataset, upregulated ferroptosis pathway genes were mainly found in the infarction-stimulated cardiac cells (border zone and fibrotic zone), particularly the cardiomyocytes and adipocytes. The ATF3 and some of its potential transcription factors (VDR, EGR3, PAX5, and SP1) can be regulated by SCFA. SCFA can attenuate erastin-induced lipid peroxidation in cardiomyocytes. SCFA treatment can also reverse erastin-induced Fe2+ increase but may strengthen the Fe2+ in the H/R model. We also precisely defined a ferroptosis subcluster of cardiomyocytes (CM09) that highly expressed FPG, ATF3, and GPRA.ConclusionThe ATF3 and the ferroptosis pathway are elevated in cardiomyocytes of injury-related cardiac regions (border zone, ischemic zone, and fibrotic zone). SCFA can attenuate cardiomyocyte ferroptosis and regulate the expression of ATF3. Our study offers novel insights into the potential targets of SCFAs in the cardiovascular system.

Dataset Information

MT1DP loaded by folate-modified liposomes sensitizes erastin-induced ferroptosis via regulating miR-365a-3p/NRF2 axis in non-small cell lung cancer cells.

Publications

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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