BIBR1532 inhibits proliferation and metastasis of esophageal squamous cancer cells by inducing telomere dysregulation  

作　　者：Qin Wang Qing-Rong Li Lei Xu Zi-Chun Yuan Xiao Liu Mao-Ju Tang Man Luo Xiao-Wu Zhong Qiang Ma Xiao-Lan Guo 

机构地区：[1]Department of Clinical Laboratory,Affiliated Hospital of North Sichuan Medical College,Nanchong 637000,Sichuan Province,China [2]School of Laboratory Medicine&Translational Medicine Research Center,North Sichuan Medical College,Nanchong 637000,Sichuan Province,China

出　　处：《World Journal of Gastrointestinal Oncology》2025年第1期214-225,共12页世界胃肠肿瘤学杂志（英文）

基　　金：Supported by the Scientific Research Development Plan Project or the Scientific Research Foundation for Advanced Talents,Affiliated Hospital of North Sichuan Medical College,No.2023MPZK017,No.2023ZD001,No.2023-2ZD002,and No.2023GC009;Science and Technology Support Program of Nanchong,No.22SXQT0001;Youth Medical Innovation Research Project,or Medical Research Project of Sichuan Province,No.Q23047 and No.S23020;Development of a Scientific Research Plan for the Doctoral Scientific Research Foundation of the North Sichuan Medical College,No.CBY22-ZDA03.

摘　　要：BACKGROUND Esophageal squamous cell carcinoma(ESCC)is a malignant tumor with high morbidity and mortality,and easy to develop resistance to chemotherapeutic agents.Telomeres are DNA-protein complexes located at the termini of chro-mosomes in eukaryotic cells,which are unreplaceable in maintaining the stability and integrity of genome.Telomerase,an RNA-dependent DNA polymerase,play vital role in telomere length maintain,targeting telomerase is a promising therapeutic strategy for cancer.KYSE150 and KYSE410 cells were cultured and exposed to various concentrations of BIBR1532.Cell viability was assessed at 48 hours and 72 hours to determine the IC50 values.The effects of BIBR1532 on ESCC cell proliferation,migration,and cellular senescence were evaluated using the cell counting kit-8 assay,plate colony formation assay,scratch assay,transwell assay,andβ-galactosidase staining,respectively.Western blotting was performed to detect the expression of RESULTS The IC50 values for KYSE150 and KYSE410 cells after 48 hours of BIBR1532 exposure were 48.53μM and 39.59μM,respectively.These values decreased to 37.22μM and 22.71μM,respectively,following a longer exposure of 72 hours.BIBR1532 exhibited dose-dependent effects on KYSE150 and KYSE410 cells,including decreased hTERT expression,inhibition of proliferation and metastasis,and induction of cellular senescence.Mechanistically,BIBR1532 upregulated the expression of the DDR protein,γ-H2AX,and activated the ataxia telangiectasia and Rad3-related protein(ATR)/check point kinase 1(CHK-1)and ataxia-telangiectasia mutated gene(ATM)/CHK2 pathways.BIBR1532 downregulated the expression of telomere-binding proteins,including telomeric-repeat binding factor 1(TRF1),TRF2,protection of telomeres 1,and TIN2-interacting protein 1.In a nude mouse xenograft model,BIBR1532 significantly suppressed tumor growth,reduced hTERT expression,and increasedγ-H2AX protein levels.Hematoxylin and eosin staining of various organs,including the heart,liver,spleen,lungs,and kidneys,revealed no appar

关 键 词：Esophageal squamous cell carcinoma BIBR1532 Human telomerase reverse transcriptase DNA damage response Telomere-binding proteins 

分 类 号：R735.1[医药卫生—肿瘤]