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

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 1...

Full description

Saved in:

Bibliographic Details
Published in:	Cell death & disease 2020-09, Vol.11 (9), p.751-751, Article 751
Main Authors:	Gai, Chengcheng, Liu, Chuanliang, Wu, Xinghan, Yu, Mengyu, Zheng, Jie, Zhang, Weifen, Lv, Shijun, Li, Wentong
Format:	Article
Language:	eng
Subjects:	Animals Antioxidants Bioavailability Carcinoma, Non-Small-Cell Lung - drug therapy Cell Line, Tumor Cell Proliferation Ectopic expression Ferroptosis - drug effects Folic acid Glutathione Humans Lipopolysaccharides Liposomes Liposomes - metabolism Lung cancer Lung Neoplasms - drug therapy Malondialdehyde Metallothionein Mice Nanoparticles NF-E2-Related Factor 2 - drug effects Non-small cell lung carcinoma Oxidative stress Piperazines - pharmacology Piperazines - therapeutic use Reactive oxygen species Ribonucleic acid RNA Small cell lung carcinoma Transcription Transfection Xenografts
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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.
ISSN:	2041-4889 2041-4889