三氧化二砷诱导的多发性骨髓瘤细胞凋亡的功能蛋白质组学研究
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摘要
多发性骨髓瘤(multiple myeloma,MM)是恶性浆细胞肿瘤,多见于中老年人,近10年来,随着我国人口老龄化日益明显,其发生率呈上升趋势,目前仍是一种不可治愈的疾病。三氧化二砷(arsenic trioxide,ATO)是中药砒霜的有效成分,20世纪70年代发现可以有效治疗急性早幼粒白血病(acute promyelocytic leukemia,APL),后来发现其在体外可以诱导多发性骨髓瘤细胞凋亡,但其作用的机制现在尚不明确。
目的:建立三氧化二砷作用前后的多发性骨髓瘤细胞系U266的蛋白质双向电泳图谱,结合质谱技术鉴定并分析差异表达蛋白,对候选表达差异蛋白进行蛋白质功能和相关研究,进一步阐明三氧化二砷诱导的多发性骨髓瘤细胞凋亡的作用机制。
方法:选用多发性骨髓瘤U266细胞系,加药细胞以ATO半数抑制量处理24小时,分别收集ATO处理和未经处理的U266细胞,提取总蛋白,建立了ATO作用前后的U266细胞的蛋白质双向电泳图谱,用ImageMaster 2D Platinum图象分析软件进行比较,以差异倍数在2倍以上的蛋白质点作为显著性差异表达蛋白质筛选标准。利用串联飞行时间质谱MALDI-TOF/TOF-MS对候选表达差异蛋白做肽质量指纹(PMF)和MS/MS质谱鉴定。应用生物信息学,通过数据库的查找分析,对差异表达蛋白进行了功能分类和初步分析。Western blot验证了热激蛋白和14-3-3ζ的表达变化,然后分别对U266细胞进行14-3-3ζ的过表达和基于RNAi的表达沉默,以及HSP90的抑制,观察ATO处理的U266细胞的变化。
结果:1.建立了ATO作用前后U266细胞系的双向凝胶电泳图谱,鉴定了84个差异表达蛋白,共76个非重复性差异。其中29个表达上调,47个表达下调,包括下调的信号转导蛋白,泛素/蛋白酶体相关蛋白和上调的细胞免疫、防御蛋白。
2.在鉴定的差异表达蛋白中,选择14-3ζ(和热激蛋白(HSP)做进一步研究。在U266细胞系中过表达14-3-3ζ能适当的削弱ATO诱导的细胞凋亡,而基于RNAi的14-3-3ζ沉默或者抑制HSP90能够提高U266细胞对ATO的敏感性。
结论:本实验分析了ATO处理前后MM细胞蛋白的变化,解释了由ATO引起的MM细胞凋亡途径。ATO诱导了MM细胞中热激蛋白的上调和14-3-3ζ及泛素/蛋白酶体相关蛋白的下调。进一步研究证实,14-3-3ζ和HSP是ATO诱导多发性骨髓瘤凋亡的潜在分子作用靶标,研究结果为探索ATO治疗多发性骨髓瘤的机理提供了理论依据,并且对临床治疗多发性骨髓瘤提出了新的治疗思路。
Multiple myeloma(MM) is an incurable plasma cell malignancy with a terminal phase marked by increased proliferation and resistance to therapy.Arsenic trioxide(ATO),an antitumor agent with a multifaceted mechanism of action,displayed clinical activity in patients with late-stage multiple myeloma.However,the precise mechanism(s) of action of ATO has not been completely elucidated.
AIM:To use proteomics to analyze the ATO-induced protein alterations in MM cell line U266 cells to investigated the molecular pathways responsible for the anticancer actions of ATO.
METHOD:We used a global proteomic-based approach to look at ATO-induced apoptosis in U266 myeloma cells.By comparing the protein,profiles of U266 cells treated by ATO to those untreated control,we identified differentially expressed proteins.Significantly regulated 14-3-3ζand heat shock proteins(HSPs) were selected for further functional studies.
RESULTS:Several clusters of proteins altered in expression in U266 Cells upon ATO treatment were identified,including down-regulated signal transduction proteins and ubiquitin/proteasome members,and up-regulated immunity and defense proteins. Overexpression of 14-3-3ζin MM cells attenuated ATO-induced cell death,whereas RNAi-based 14-3-3ζknock-down or the inhibition of HSP90 enhanced U266 cell sensitivity to the ATO induction.
CONCLUSIONS:The current study characterized the molecular sequelae of ATO treatment in MM and defined apoptotic pathways triggered by this agent.Our results showed that ATO induced up-regulation of HSPs and down-regulation of 14-3-3ζand the members of proteasome/ubiquitin system.Specifically,our in-depth functional studies suggested a dual apoptotic mechanism induced by ATO in MM cells,with a pivotal role for the 14-3-3ζin one arm and the regulation of ubiquitination-proteasome pathway in the other.
目的:建立三氧化二砷作用前后的多发性骨髓瘤细胞系U266的蛋白质双向电泳图谱,结合质谱技术鉴定并分析差异表达蛋白,对候选表达差异蛋白进行蛋白质功能和相关研究,进一步阐明三氧化二砷诱导的多发性骨髓瘤细胞凋亡的作用机制。
方法:选用多发性骨髓瘤U266细胞系,加药细胞以ATO半数抑制量处理24小时,分别收集ATO处理和未经处理的U266细胞,提取总蛋白,建立了ATO作用前后的U266细胞的蛋白质双向电泳图谱,用ImageMaster 2D Platinum图象分析软件进行比较,以差异倍数在2倍以上的蛋白质点作为显著性差异表达蛋白质筛选标准。利用串联飞行时间质谱MALDI-TOF/TOF-MS对候选表达差异蛋白做肽质量指纹(PMF)和MS/MS质谱鉴定。应用生物信息学,通过数据库的查找分析,对差异表达蛋白进行了功能分类和初步分析。Western blot验证了热激蛋白和14-3-3ζ的表达变化,然后分别对U266细胞进行14-3-3ζ的过表达和基于RNAi的表达沉默,以及HSP90的抑制,观察ATO处理的U266细胞的变化。
结果:1.建立了ATO作用前后U266细胞系的双向凝胶电泳图谱,鉴定了84个差异表达蛋白,共76个非重复性差异。其中29个表达上调,47个表达下调,包括下调的信号转导蛋白,泛素/蛋白酶体相关蛋白和上调的细胞免疫、防御蛋白。
2.在鉴定的差异表达蛋白中,选择14-3ζ(和热激蛋白(HSP)做进一步研究。在U266细胞系中过表达14-3-3ζ能适当的削弱ATO诱导的细胞凋亡,而基于RNAi的14-3-3ζ沉默或者抑制HSP90能够提高U266细胞对ATO的敏感性。
结论:本实验分析了ATO处理前后MM细胞蛋白的变化,解释了由ATO引起的MM细胞凋亡途径。ATO诱导了MM细胞中热激蛋白的上调和14-3-3ζ及泛素/蛋白酶体相关蛋白的下调。进一步研究证实,14-3-3ζ和HSP是ATO诱导多发性骨髓瘤凋亡的潜在分子作用靶标,研究结果为探索ATO治疗多发性骨髓瘤的机理提供了理论依据,并且对临床治疗多发性骨髓瘤提出了新的治疗思路。
Multiple myeloma(MM) is an incurable plasma cell malignancy with a terminal phase marked by increased proliferation and resistance to therapy.Arsenic trioxide(ATO),an antitumor agent with a multifaceted mechanism of action,displayed clinical activity in patients with late-stage multiple myeloma.However,the precise mechanism(s) of action of ATO has not been completely elucidated.
AIM:To use proteomics to analyze the ATO-induced protein alterations in MM cell line U266 cells to investigated the molecular pathways responsible for the anticancer actions of ATO.
METHOD:We used a global proteomic-based approach to look at ATO-induced apoptosis in U266 myeloma cells.By comparing the protein,profiles of U266 cells treated by ATO to those untreated control,we identified differentially expressed proteins.Significantly regulated 14-3-3ζand heat shock proteins(HSPs) were selected for further functional studies.
RESULTS:Several clusters of proteins altered in expression in U266 Cells upon ATO treatment were identified,including down-regulated signal transduction proteins and ubiquitin/proteasome members,and up-regulated immunity and defense proteins. Overexpression of 14-3-3ζin MM cells attenuated ATO-induced cell death,whereas RNAi-based 14-3-3ζknock-down or the inhibition of HSP90 enhanced U266 cell sensitivity to the ATO induction.
CONCLUSIONS:The current study characterized the molecular sequelae of ATO treatment in MM and defined apoptotic pathways triggered by this agent.Our results showed that ATO induced up-regulation of HSPs and down-regulation of 14-3-3ζand the members of proteasome/ubiquitin system.Specifically,our in-depth functional studies suggested a dual apoptotic mechanism induced by ATO in MM cells,with a pivotal role for the 14-3-3ζin one arm and the regulation of ubiquitination-proteasome pathway in the other.
引文
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