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作者单位

Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment，Tianjin Lung Cancer Institute，Tianjin Medical University General Hospital，Tianjin 300052，China；Department of Anesthesiology，Tianjin First Central Hospital，Tianjin 300192，China；Department of Clinical Laboratory，Shandong Cancer Hospital and Institute，Shandong First Medical University and Shandong Academy of Medical Sciences，Jinan 250117，China；Core Facility Center，Tianjin Medical University General Hospital，Tianjin 300052，China

刊名

中国药理学报(英文版)

年份

2024

卷号

第45卷

期号

第3期

页码

619-632

ISSN

1671-4083

关键词

non-small cell lung cancer metastasis phenethyl isothiocyanate m6A methylation FTO TLE1

摘要

N6-methyladenosinemodification is a prevalent RNA epigenetic modification,which plays a crucial role in tumor progression including metastasis.Isothiocyanatesare natural compounds and inhibit the tumorigenesis of various cancers.Our previous studies show that ITCs inhibit the proliferation and metastasis of non-small cell lung cancercells,and have synergistic effects with chemotherapy drugs.In this study,we investigated the molecular mechanisms underlying the inhibitory effects of ITCs on cancer...更多

N6-methyladenosinemodification is a prevalent RNA epigenetic modification,which plays a crucial role in tumor progression including metastasis.Isothiocyanatesare natural compounds and inhibit the tumorigenesis of various cancers.Our previous studies show that ITCs inhibit the proliferation and metastasis of non-small cell lung cancercells,and have synergistic effects with chemotherapy drugs.In this study,we investigated the molecular mechanisms underlying the inhibitory effects of ITCs on cancer cell metastasis.We showed that phenethyl isothiocyanatedose-dependently inhibited the cell viability of both NSCLC cell lines H1299 and H226 with IC50 values of 17.6 and 15.2 μM,respectively.Furthermore,PEITC dose-dependently inhibited the invasion and migration of H1299 and H226 cells.We demonstrated that PEITC treatment dose-dependently increased m6A methylation levels and inhibited the expression of the m6A demethylase fat mass and obesity-associated proteinin H1299 and H226 cells.Knockdown of FTO significantly increased m6A methylation in H1299 and H226 cells,impaired their abilities of invasion and migration in vitro,and enhanced the inhibition of PEITC on tumor growth in vivo.Overexpression of FTO promoted the migration of NSCLC cells,and also mitigated the inhibitory effect of PEITC on migration of NSCLC cells.Furthermore,we found that FTO regulated the mRNA m6A modification of a transcriptional co-repressor Transducin-Like Enhancer of split-1and further affected its stability and expression.TCGA database analysis revealed TLE1 was upregulated in NSCLC tissues compared to normal tissues,which might be correlated with the metastasis status.Moreover,we showed that PEITC suppressed the migration of NSCLC cells by inhibiting TLE1 expression and downstream Akt/NF-κB pathway.This study reveals a novel mechanism underlying ITC's inhibitory effect on metastasis of lung cancer cells,and provided valuable information for developing new therapeutics for lung cancer by targeting m6A methylation.收起

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