Background:Apolipoprotein B mRNA editing catalytic polypeptide(APOBEC),an endogenous mutator,induces DNA damage and activates the ataxia telangiectasia and Rad3-related(ATR)-checkpoint kinase 1(Chk1)pathway.Although c...Background:Apolipoprotein B mRNA editing catalytic polypeptide(APOBEC),an endogenous mutator,induces DNA damage and activates the ataxia telangiectasia and Rad3-related(ATR)-checkpoint kinase 1(Chk1)pathway.Although cisplatin-based therapy is the mainstay for muscle-invasive bladder cancer(MIBC),it has a poor survival rate.Therefore,this study aimed to evaluate the efficacy of an ATR inhibitor combined with cisplatin in the treatment of APOBEC catalytic subunit 3B(APOBEC3B)expressing MIBC.Methods:Immunohistochemical staining was performed to analyze an association between APOBEC3B and ATR in patients with MIBC.The APOBEC3B expression in MIBC cell lines was assessed using real-time polymerase chain reaction and western blot analysis.Western blot analysis was performed to confirm differences in phosphorylated Chk1(pChk1)expression according to the APOBEC3B expression.Cell viability and apoptosis analyses were performed to examine the anti-tumor activity of ATR inhibitors combined with cisplatin.Results:There was a significant association between APOBEC3B and ATR expression in the tumor tissues obtained from patients with MIBC.Cells with higher APOBEC3B expression showed higher pChk1 expression than cells expressing low APOBEC3B levels.Combination treatment of ATR inhibitor and cisplatin inhibited cell growth in MIBC cells with a higher APOBEC3B expression.Compared to cisplatin single treatment,combination treatment induced more apoptotic cell death in the cells with higher APOBEC3B expression.Conclusion:Our study shows that APOBEC3B’s higher expression status can enhance the sensitivity of MIBC to cisplatin upon ATR inhibition.This result provides new insight into appropriate patient selection for the effective application of ATR inhibitors in MIBC.展开更多
载脂蛋白B m RNA编辑酶催化多肽3G(apolipoprotein B m RNA editing enzyme catalytic polypeptide-like 3G,APOBEC3G)是一种天然抗病毒因子,目前研究证明其具有抗乙肝病毒的作用。它可能通过影响HBV DNA逆转录、诱导HBV DNA超突变、包...载脂蛋白B m RNA编辑酶催化多肽3G(apolipoprotein B m RNA editing enzyme catalytic polypeptide-like 3G,APOBEC3G)是一种天然抗病毒因子,目前研究证明其具有抗乙肝病毒的作用。它可能通过影响HBV DNA逆转录、诱导HBV DNA超突变、包装到HBV病毒粒子中、参与干扰素的抗病毒作用等方式起到抗乙肝病毒的作用。它为新型抗病毒药物的开发和机体天然免疫机制的研究开拓了新的方向,可能对未来的HBV防治提供新的线索并产生重要影响。展开更多
基金supported by St.Vincent’s Hospital,the Research Institute of Medical Science(Grant Number:SVHR-2021-03).
文摘Background:Apolipoprotein B mRNA editing catalytic polypeptide(APOBEC),an endogenous mutator,induces DNA damage and activates the ataxia telangiectasia and Rad3-related(ATR)-checkpoint kinase 1(Chk1)pathway.Although cisplatin-based therapy is the mainstay for muscle-invasive bladder cancer(MIBC),it has a poor survival rate.Therefore,this study aimed to evaluate the efficacy of an ATR inhibitor combined with cisplatin in the treatment of APOBEC catalytic subunit 3B(APOBEC3B)expressing MIBC.Methods:Immunohistochemical staining was performed to analyze an association between APOBEC3B and ATR in patients with MIBC.The APOBEC3B expression in MIBC cell lines was assessed using real-time polymerase chain reaction and western blot analysis.Western blot analysis was performed to confirm differences in phosphorylated Chk1(pChk1)expression according to the APOBEC3B expression.Cell viability and apoptosis analyses were performed to examine the anti-tumor activity of ATR inhibitors combined with cisplatin.Results:There was a significant association between APOBEC3B and ATR expression in the tumor tissues obtained from patients with MIBC.Cells with higher APOBEC3B expression showed higher pChk1 expression than cells expressing low APOBEC3B levels.Combination treatment of ATR inhibitor and cisplatin inhibited cell growth in MIBC cells with a higher APOBEC3B expression.Compared to cisplatin single treatment,combination treatment induced more apoptotic cell death in the cells with higher APOBEC3B expression.Conclusion:Our study shows that APOBEC3B’s higher expression status can enhance the sensitivity of MIBC to cisplatin upon ATR inhibition.This result provides new insight into appropriate patient selection for the effective application of ATR inhibitors in MIBC.
文摘载脂蛋白B m RNA编辑酶催化多肽3G(apolipoprotein B m RNA editing enzyme catalytic polypeptide-like 3G,APOBEC3G)是一种天然抗病毒因子,目前研究证明其具有抗乙肝病毒的作用。它可能通过影响HBV DNA逆转录、诱导HBV DNA超突变、包装到HBV病毒粒子中、参与干扰素的抗病毒作用等方式起到抗乙肝病毒的作用。它为新型抗病毒药物的开发和机体天然免疫机制的研究开拓了新的方向,可能对未来的HBV防治提供新的线索并产生重要影响。
