Long non-coding RNAs(lncRNAs)have been implicated in cancer progression and drug resistance development.Moreover,there is evidence that lncRNA HOX transcript antisense intergenic RNA(HOTAIR)is involved in colorectal c...Long non-coding RNAs(lncRNAs)have been implicated in cancer progression and drug resistance development.Moreover,there is evidence that lncRNA HOX transcript antisense intergenic RNA(HOTAIR)is involved in colorectal cancer(CRC)progression.The present study aimed to examine the functional role of lncRNA HOTAIR in conferring radiotherapy resistance in CRC cells,as well as the underlying mechanism.The relative expression levels of HOTAIR were examined in 70 pairs of CRC tumor and para-cancerous tissues,as well as in radiosensitive and radioresistant samples.The correlations between HOTAIR expression levels and clinical features of patients with CRC were assessed using the Chi-square test.Functional assays such as cell proliferation,colony formation and apoptosis assays were conducted to determine the radiosensitivity in CRC cells with HOTAIR silencing after treatment with different doses of radiation.RNA pull-down assay andfluorescence in situ hybridization(FISH)were used to determine the interaction between HOTAIR and DNA damage response mediator ataxia-telangiectasia mutated-and Rad3-related(ATR).HOTAIR was significantly upregulated in CRC tumor tissues,especially in radioresistant tumor samples.The elevated expression of HOTAIR was correlated with more advanced histological grades,distance metastasis and the poor prognosis in patients with CRC.Silencing HOTAIR suppressed the proliferation and promoted apoptosis and radiosensitivity in CRC cells.HOTAIR knockdown also inhibited the tumorigenesis of CRC cells and enhanced the sensitivity to radiotherapy in a mouse xenograft model.Moreover,the data showed that HOTAIR could interact with ATR to regulate the DNA damage repair signaling pathway.Silencing HOTAIR impaired the ATR-ATR interacting protein(ATRIP)complex and signaling in cell cycle progression.Collectively,the present results indicate that lncRNA HOTAIR facilitates the DNA damage response pathway and promotes radioresistance in CRC cells by targeting ATR.展开更多
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
DNA损伤应答(DNAdamageresponse,DDR)机制包括检测DNA损伤,阻滞细胞周期和启动DNA修复。共济失调毛细血管扩张和Rad3相关激酶(ataxia telangiectasia and Rad3-related,ATR)是DDR核心的关键激酶,负责感知复制应激(replica-tion stress,...DNA损伤应答(DNAdamageresponse,DDR)机制包括检测DNA损伤,阻滞细胞周期和启动DNA修复。共济失调毛细血管扩张和Rad3相关激酶(ataxia telangiectasia and Rad3-related,ATR)是DDR核心的关键激酶,负责感知复制应激(replica-tion stress,RS)并将其信号传导至S和G2/M检查点以启动DNA修复。在肿瘤细胞中G1检查点缺失和癌基因的激活,导致癌症细胞更多进入RS增加的S期。因此,肿瘤细胞更加依赖S和G2/M检查点,使其成为一个有吸引力的靶点。ATR抑制剂是目前抗肿瘤药物开发的热点,部分ATR抑制剂目前已经进入临床试验阶段。本综述旨在总结支持ATR抑制剂作为单药以及与化疗、放疗和新型靶向药物(如PARP抑制剂)联合使用的临床试验数据,并讨论目前ATR抑制剂开发和生物标志物探索中面临的挑战。展开更多
从分子库中筛选出潜在活性化合物,是药物发现常用的方法。然而,随着化学空间的不断探索,目前已有超过数十亿分子的化合物库,仅仅依靠分子对接已不足以从超大化合物库中对特定靶点抑制剂进行快速筛选。本研究提出了一种筛选潜在活性化合...从分子库中筛选出潜在活性化合物,是药物发现常用的方法。然而,随着化学空间的不断探索,目前已有超过数十亿分子的化合物库,仅仅依靠分子对接已不足以从超大化合物库中对特定靶点抑制剂进行快速筛选。本研究提出了一种筛选潜在活性化合物的方法,通过计算物理化学性质相似性、构建机器学习预测模型以及分子对接等步骤,对含有55亿分子的候选化合物库进行过滤筛选,最终得到51个具有共济失调毛细血管扩张突变基因和Rad3相关蛋白(ataxia telangiectasia-mutated and Rad3-related,ATR)激酶潜在抑制活性的化合物。该方法为从超大库中快速筛选新颖潜在活性分子提供了有效途径。展开更多
Intensive cancer treatment with drug combination is widely exploited in the clinic but suffers from inconsistent pharmacokinetics among different therapeutic agents.To overcome it,the emerging nanomedicine offers an u...Intensive cancer treatment with drug combination is widely exploited in the clinic but suffers from inconsistent pharmacokinetics among different therapeutic agents.To overcome it,the emerging nanomedicine offers an unparalleled opportunity for encapsulating multiple drugs in a nano-carrier.Herein,a two-step super-assembled strategy was performed to unify the pharmacokinetics of a peptide and a small molecular compound.In this proof-of-concept study,the bioinformatics analysis firstly revealed the potential synergies towards hepatoma therapy for the associative inhibition of exportin 1(XPO1)and ataxia telangiectasia mutated-Rad3-related(ATR),and then a super-assembled nano-pill(gold nano drug carrier loaded AZD6738 and 97110 amino acids of apoptin(AP)(AA@G))was constructed through camouflaging AZD6738(ATR small-molecule inhibitor)-binding human serum albumin onto the AP-Au supramolecular nanoparticle.As expected,both in vitro and in vivo experiment results verified that the AA@G possessed extraordinary biocompatibility and enhanced therapeutic effect through inducing cell cycle arrest,promoting DNA damage and inhibiting DNA repair of hepatoma cell.This work not only provides a co-delivery strategy for intensive liver cancer treatment with the clinical translational potential,but develops a common approach to unify the pharmacokinetics of peptide and small-molecular compounds,thereby extending the scope of drugs for developing the advanced combination therapy.展开更多
基金This study was supported by the Inner Mongolia Science and Technology Department Science and Technology Research Project(No.2021GG0270)National Natural Science Foundation of China(81860534)+5 种基金Natural Science Foundation of Inner Mongolia(2021MS08152)Program for Young Talents of Science and Technology in Universities of Inner Mongolia Autonomous Region(NJYT22004)Scientific and Technological Innovative Research Team for Inner Mongolia Medical University of Transformation Application of Organoid in Medical and Industrial Interdiscipline(YKD2022TD002)Major Project of Inner Mongolia Medical University(YKD2022 ZD002)Radiobiology System and Team Construction of Radiotherapy for Inner Mongolia Medical University(YKD2022XK014)Key Laboratoy of Radiation Physics and Biology of Inner Mongolia Medical University(PIKY2023030).
文摘Long non-coding RNAs(lncRNAs)have been implicated in cancer progression and drug resistance development.Moreover,there is evidence that lncRNA HOX transcript antisense intergenic RNA(HOTAIR)is involved in colorectal cancer(CRC)progression.The present study aimed to examine the functional role of lncRNA HOTAIR in conferring radiotherapy resistance in CRC cells,as well as the underlying mechanism.The relative expression levels of HOTAIR were examined in 70 pairs of CRC tumor and para-cancerous tissues,as well as in radiosensitive and radioresistant samples.The correlations between HOTAIR expression levels and clinical features of patients with CRC were assessed using the Chi-square test.Functional assays such as cell proliferation,colony formation and apoptosis assays were conducted to determine the radiosensitivity in CRC cells with HOTAIR silencing after treatment with different doses of radiation.RNA pull-down assay andfluorescence in situ hybridization(FISH)were used to determine the interaction between HOTAIR and DNA damage response mediator ataxia-telangiectasia mutated-and Rad3-related(ATR).HOTAIR was significantly upregulated in CRC tumor tissues,especially in radioresistant tumor samples.The elevated expression of HOTAIR was correlated with more advanced histological grades,distance metastasis and the poor prognosis in patients with CRC.Silencing HOTAIR suppressed the proliferation and promoted apoptosis and radiosensitivity in CRC cells.HOTAIR knockdown also inhibited the tumorigenesis of CRC cells and enhanced the sensitivity to radiotherapy in a mouse xenograft model.Moreover,the data showed that HOTAIR could interact with ATR to regulate the DNA damage repair signaling pathway.Silencing HOTAIR impaired the ATR-ATR interacting protein(ATRIP)complex and signaling in cell cycle progression.Collectively,the present results indicate that lncRNA HOTAIR facilitates the DNA damage response pathway and promotes radioresistance in CRC cells by targeting ATR.
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DNA损伤应答(DNAdamageresponse,DDR)机制包括检测DNA损伤,阻滞细胞周期和启动DNA修复。共济失调毛细血管扩张和Rad3相关激酶(ataxia telangiectasia and Rad3-related,ATR)是DDR核心的关键激酶,负责感知复制应激(replica-tion stress,RS)并将其信号传导至S和G2/M检查点以启动DNA修复。在肿瘤细胞中G1检查点缺失和癌基因的激活,导致癌症细胞更多进入RS增加的S期。因此,肿瘤细胞更加依赖S和G2/M检查点,使其成为一个有吸引力的靶点。ATR抑制剂是目前抗肿瘤药物开发的热点,部分ATR抑制剂目前已经进入临床试验阶段。本综述旨在总结支持ATR抑制剂作为单药以及与化疗、放疗和新型靶向药物(如PARP抑制剂)联合使用的临床试验数据,并讨论目前ATR抑制剂开发和生物标志物探索中面临的挑战。
文摘从分子库中筛选出潜在活性化合物,是药物发现常用的方法。然而,随着化学空间的不断探索,目前已有超过数十亿分子的化合物库,仅仅依靠分子对接已不足以从超大化合物库中对特定靶点抑制剂进行快速筛选。本研究提出了一种筛选潜在活性化合物的方法,通过计算物理化学性质相似性、构建机器学习预测模型以及分子对接等步骤,对含有55亿分子的候选化合物库进行过滤筛选,最终得到51个具有共济失调毛细血管扩张突变基因和Rad3相关蛋白(ataxia telangiectasia-mutated and Rad3-related,ATR)激酶潜在抑制活性的化合物。该方法为从超大库中快速筛选新颖潜在活性分子提供了有效途径。
基金supported by the National Natural Science Foundation of China(Grant Nos.:81272488 and 81602802)the Shaanxi Province Innovation Capacity Support Program(Grant No.:2018TD-002).
文摘Intensive cancer treatment with drug combination is widely exploited in the clinic but suffers from inconsistent pharmacokinetics among different therapeutic agents.To overcome it,the emerging nanomedicine offers an unparalleled opportunity for encapsulating multiple drugs in a nano-carrier.Herein,a two-step super-assembled strategy was performed to unify the pharmacokinetics of a peptide and a small molecular compound.In this proof-of-concept study,the bioinformatics analysis firstly revealed the potential synergies towards hepatoma therapy for the associative inhibition of exportin 1(XPO1)and ataxia telangiectasia mutated-Rad3-related(ATR),and then a super-assembled nano-pill(gold nano drug carrier loaded AZD6738 and 97110 amino acids of apoptin(AP)(AA@G))was constructed through camouflaging AZD6738(ATR small-molecule inhibitor)-binding human serum albumin onto the AP-Au supramolecular nanoparticle.As expected,both in vitro and in vivo experiment results verified that the AA@G possessed extraordinary biocompatibility and enhanced therapeutic effect through inducing cell cycle arrest,promoting DNA damage and inhibiting DNA repair of hepatoma cell.This work not only provides a co-delivery strategy for intensive liver cancer treatment with the clinical translational potential,but develops a common approach to unify the pharmacokinetics of peptide and small-molecular compounds,thereby extending the scope of drugs for developing the advanced combination therapy.
