RRC ID 72417
Author Wang Q, Chen C, Xu X, Shu C, Cao C, Wang Z, Fu Y, Xu L, Xu K, Xu J, Xia A, Wang B, Xu G, Zou X, Su R, Kang W, Xue Y, Mo R, Sun B, Wang S.
Title APAF1-Binding Long Noncoding RNA Promotes Tumor Growth and Multidrug Resistance in Gastric Cancer by Blocking Apoptosome Assembly.
Journal Adv Sci (Weinh)
Abstract Chemotherapeutics remain the first choice for advanced gastric cancers (GCs). However, drug resistance and unavoidable severe toxicity lead to chemotherapy failure and poor prognosis. Long noncoding RNAs (lncRNAs) play critical roles in tumor progression in many cancers, including GC. Here, through RNA screening, an apoptotic protease-activating factor 1 (APAF1)-binding lncRNA (ABL) that is significantly elevated in cancerous GC tissues and an independent prognostic factor for GC patients is identified. Moreover, ABL overexpression inhibits GC cell apoptosis and promotes GC cell survival and multidrug resistance in GC xenograft and organoid models. Mechanistically, ABL directly binds to the RNA-binding protein IGF2BP1 via its KH1/2 domain, and then IGF2BP1 further recognizes the METTL3-mediated m6A modification on ABL, which maintains ABL stability. In addition, ABL can bind to the WD1/WD2 domain of APAF1, which competitively prevent cytochrome c from interacting with APAF1, blocking apoptosome assembly and caspase-9/3 activation; these events lead to resistance to cell death in GC cells. Intriguingly, targeting ABL using encapsulated liposomal siRNA can significantly enhance the sensitivity of GC cells to chemotherapy. Collectively, the results suggest that ABL can be a potential prognostic biomarker and therapeutic target in GC.
Volume 9(28)
Pages e2201889
Published 2022-10-1
DOI 10.1002/advs.202201889
PMID 35975461
PMC PMC9534967
MeSH Apoptosis / genetics Apoptosomes / metabolism Apoptotic Protease-Activating Factor 1 / genetics Apoptotic Protease-Activating Factor 1 / metabolism Biomarkers Caspase 9 / metabolism Cytochromes c / metabolism Cytochromes c / therapeutic use Drug Resistance, Multiple Humans Methyltransferases / metabolism Methyltransferases / therapeutic use RNA, Long Noncoding* / genetics RNA, Small Interfering / therapeutic use Stomach Neoplasms* / drug therapy Stomach Neoplasms* / genetics Stomach Neoplasms* / metabolism
IF 15.84
Human and Animal Cells MKN45(RCB1001)