抑制自噬增加阿霉素对骨髓瘤细胞的促凋亡活性
摘要
研究背景和目的:自噬作为广泛存在于真核细胞中的生命现象,是细胞成分更新、发育、分化的重要调控机制,对维持蛋白代谢平衡及细胞内环境稳定具有重要意义。自噬是目前细胞生物学研究的热点之一,自噬与肿瘤关系的研究更被广泛关注。1999年Beth Levine等发现Beclin1单等位基因缺失致乳腺癌等患病率升高,人们认为自噬与肿瘤发生相关,并探寻诱导自噬治疗肿瘤。但进一步研究发现,自噬具有两面性,某些情况下,诱导自噬可以抑制肿瘤生长,并致自噬相关性细胞死亡;但更多情况下,肿瘤细胞可利用自噬以应对缺氧、营养匮乏及清除氧自由基、损伤的线粒体等,从而保护瘤细胞。值得注意的是:自噬对肿瘤的影响具有细胞类型及剌激依赖性,在不同的肿瘤类型与剌激条件下,自噬所起作用可能不同。多发性骨髓瘤(MM)细胞因分泌大量免疫球蛋白,蛋白质代谢极为旺盛,而自噬作为蛋白质降解代谢主要途径之一,对MM细胞死亡过程中究竟起着什么样的作用,目前尚无前人的经验可循。本课题以MM细胞系RPMI8226、H929及原代细胞为研究材料,探寻自噬对阿霉素(DOX)等化疗药物的促MM细胞凋亡的活性及其相关机制。
方法和结果: 1.MTT法首先探寻自噬抑制剂羟氯喹(HCQ)或自噬激活剂雷帕霉素(RAPA)单药对RPMI8226及H929细胞的影响,以明确其剂量-效应关系;结果表明羟氯喹能够抑制两种细胞的增殖,并呈浓度依赖性,而雷帕霉素对细胞增殖基本无影响。2.流式细胞术发现,亚细胞毒剂量的自噬抑制剂羟氯喹、3-methlyadenine (3-MA)、Bafilomycin A1(BAF),与阿霉素、顺铂(DDP)、米托蒽醌(MIT)、马法兰(MEL)等合用均可产生增敏作用,与单药相比差异显著(P<0.05);而与长春新碱(VCR)、Bortezomib(BOR)、足叶乙甙(VP-16)等联用则无效(P>0.05)。3.透射电镜证实: 3MA单药处理组及未处理组自噬泡少见,羟氯喹+阿霉素、BAF+阿霉素组及雷帕霉素阳性对照组可见到大量自噬泡,羟氯喹、BAF及阿霉素单用组可见中等量自噬泡出现,3-MA+阿霉素联用组仅见少量自噬泡。4.内源性LC3免疫荧光染色显示,羟氯喹+阿霉素、BAF+阿霉素及雷帕霉素处理组MM细胞胞浆可见大量颗粒状荧光,羟氯喹、BAF、阿霉素单用组仅有中等量颗粒状荧光,而3-MA及3-MA+阿霉素组胞浆荧光信号基本呈弥散分布,类似于未处理对照组。5. Western blot证实:①阿霉素单药处理RPMI8226及H929细胞后8、12、24、36h,自噬蛋白Beclin1、Atg5、LC3-II表达渐升高,说明阿霉素诱导自噬活化;②Beclin1、Atg5、LC3-II表达分析表明,自噬抑制剂3-MA、羟氯喹及BAF的化学增敏作用分别与其对MM细胞自噬反应的早期抑制(阻断自噬体膜形成)与晚期抑制(抑制自噬体与溶酶体融合)有关。③凋亡蛋白caspase-3及PARP检测表明,自噬抑制剂与阿霉素联用凋亡蛋白表达高于单用阿霉素组。5. siRNA技术证明:特异性Beclin1及Atg5 siRNA导入RPMI8226及H929细胞致Beclin1及Atg5沉默,亦可增加阿霉素诱导的MM凋亡。6.小鼠模型证明:体内环境下,抑制自噬亦可增加阿霉素抑MM效应。
结论:1.阿霉素能够诱导MM凋亡同时诱发自噬反应,自噬是瘤细胞应对DNA损伤应激的一种保护性反应;2.化学抑制剂及siRNA抑制自噬,均可增加阿霉素诱导的MM系及原代MM细胞凋亡;3.体内动物模型下,抑制自噬亦可增加阿霉素抑MM效应。
Background and Aim: As a major intracellular degradation system that is found ubiquitously in eukaryotes, autophagy plays a key role in maintaining protein metabolic equilibrium and cell homeostasis, and in regulating cellular constituent recycleing, cell development and differentiation. Autophagy is one of research hot spots in cytobiology at present, furthermore the relationship between autophagy and tumor is attracting great attention. Since Beth Levine ea al demonstrates that human cells that carry monoallelic deletions of the Beclin1/ATG6 gene are tumorigenic, autophagy has been considered as a tumor suppressor, and inducing autophagy is attempted to cancer therapy. But further investigations find that autophagy has dual role in cancer, in some circumstances, inducing autophagy may inhibit tumor cell growth, and result in autophagic cell death; but in most circumstances, autophagy may function as a cytoprotective mechanism by responsing to stress situations including hypoxia, low energy, oxidative stress and damaged mitochondria. Furthermore autophagy is tumor cell type- and stress dependent, that is, In different cell type or different stress mode, the role or function of autophagy changes. Myeloma cells are featured by exceedingly active protein metabolism such as synthesis and secretion of immunoglobulin, and as one of major protein metabolism pathways, what`s the function of autophagy in myeloma cells? There is no past experience at present. Based on the background above, in this study, by means of the model of myeloma cells (RPMI8226 and H929 and primary cells) , we try to explore the effects of autophagy on cell apoptosis induced by DOX and the correlateing mechanism.
Methods and Results: 1. In our work, MTT assays showed that autophagy inhibitor hydroxychloroquine (HCQ) could inhibit proliferation of RPMI8226 and H929 cells by dose-dependent manner in vitro. While autophagy inducer rapamycin had no effects on myeloma cell proliferation.2. Flow cytometer (FCM) displayed that autophagy inhibition by HCQ, 3-methlyadenine(3-MA) or bafilomycin A1 could enhance doxorubicin(DOX), cisplatin(DDP), mitoxantone(MIT), or melphalan(MEL) induced myeloma cell apoptosis repectively ( P < 0.05), while could not enhance vincristine(VCR), etoposide(VP-16) induced cell apoptosis(P>0.05).3. Autophagic morphology of myeloma cells was monitored by Electron microscopy and fluorescence microscopy.①By electron microscopy, it showed that the autophagosome amounts in untreated, 3-MA treated and 3-MA combined with DOX treated cells were scanty, moderate in HCQ ,BAF, or DOX singly treated cells, and abundent in HCQ or BAF combined with DOX treated cells, and also abundant in positive control: rapamycin treated cells.②LC3-FITC had been used to monitor autophagy by immunofluorescence. It showed that there are a high level of LC3 puncta in HCQ+DOX or BAF +DOX treated cells, and in rapamycin treated cells, moderate level in HCQ, BAF, or DOX singly treated cells, and low level in 3-MA+DOX, and there was diffuse fluorescence in untreated or 3-MA treated cells. 4. Western blot showed:①the amount of autophagic proteins Beclin1、Atg5、LC3-II increased gradually after RPMI8226 and H929 cells were treated with DOX for 0, 4, 8, 12h respectively, which indicated that autophagy was induced by DOX;②By means of analysis of express levels of Beclin1、Atg5、LC3-II after autophagy inhibitor HCQ, BAF or 3-MA combined with DOX, It showed that chemical sensitization of HCQ and BAF was due to post-sequestration step inhibition(by blocking fusion autophagosome with lysosome) to autophagy of myeloma cells, while 3-MA was due to sequestration inhibition.③Express levels of apoptosis protein caspase-3 and PARP treated by autophagy inhibitor HCQ, BAF or 3-MA combined with DOX increased compared with treated by DOX singly, which indicated that autophagy inhibition enhanced apoptosis induced by DOX. 5. The apoptosis induced by DOX also was enhanced by specific Beclin1 siRNA or Atg5 siRNA in H929 and RPMI8226 cells. 6. It was demonstrated in myeloma mouse model that in vivo autophagy inhibition also enhanced inhibition of tumor growth induced by DOX.
Conclusions: 1.Autophagy as a protective mechanism responses to the apoptosis induced by DOX . 2. Autophagy inhibition by chemical inhibitor or specific siRNA, could enhance the apoptosis induced by DOX in myeloma cell lines or primary cells; 3. In myeloma mouse models, autophagy inhibition also enhanced inhibition of tumor growth induced by DOX.
方法和结果: 1.MTT法首先探寻自噬抑制剂羟氯喹(HCQ)或自噬激活剂雷帕霉素(RAPA)单药对RPMI8226及H929细胞的影响,以明确其剂量-效应关系;结果表明羟氯喹能够抑制两种细胞的增殖,并呈浓度依赖性,而雷帕霉素对细胞增殖基本无影响。2.流式细胞术发现,亚细胞毒剂量的自噬抑制剂羟氯喹、3-methlyadenine (3-MA)、Bafilomycin A1(BAF),与阿霉素、顺铂(DDP)、米托蒽醌(MIT)、马法兰(MEL)等合用均可产生增敏作用,与单药相比差异显著(P<0.05);而与长春新碱(VCR)、Bortezomib(BOR)、足叶乙甙(VP-16)等联用则无效(P>0.05)。3.透射电镜证实: 3MA单药处理组及未处理组自噬泡少见,羟氯喹+阿霉素、BAF+阿霉素组及雷帕霉素阳性对照组可见到大量自噬泡,羟氯喹、BAF及阿霉素单用组可见中等量自噬泡出现,3-MA+阿霉素联用组仅见少量自噬泡。4.内源性LC3免疫荧光染色显示,羟氯喹+阿霉素、BAF+阿霉素及雷帕霉素处理组MM细胞胞浆可见大量颗粒状荧光,羟氯喹、BAF、阿霉素单用组仅有中等量颗粒状荧光,而3-MA及3-MA+阿霉素组胞浆荧光信号基本呈弥散分布,类似于未处理对照组。5. Western blot证实:①阿霉素单药处理RPMI8226及H929细胞后8、12、24、36h,自噬蛋白Beclin1、Atg5、LC3-II表达渐升高,说明阿霉素诱导自噬活化;②Beclin1、Atg5、LC3-II表达分析表明,自噬抑制剂3-MA、羟氯喹及BAF的化学增敏作用分别与其对MM细胞自噬反应的早期抑制(阻断自噬体膜形成)与晚期抑制(抑制自噬体与溶酶体融合)有关。③凋亡蛋白caspase-3及PARP检测表明,自噬抑制剂与阿霉素联用凋亡蛋白表达高于单用阿霉素组。5. siRNA技术证明:特异性Beclin1及Atg5 siRNA导入RPMI8226及H929细胞致Beclin1及Atg5沉默,亦可增加阿霉素诱导的MM凋亡。6.小鼠模型证明:体内环境下,抑制自噬亦可增加阿霉素抑MM效应。
结论:1.阿霉素能够诱导MM凋亡同时诱发自噬反应,自噬是瘤细胞应对DNA损伤应激的一种保护性反应;2.化学抑制剂及siRNA抑制自噬,均可增加阿霉素诱导的MM系及原代MM细胞凋亡;3.体内动物模型下,抑制自噬亦可增加阿霉素抑MM效应。
Background and Aim: As a major intracellular degradation system that is found ubiquitously in eukaryotes, autophagy plays a key role in maintaining protein metabolic equilibrium and cell homeostasis, and in regulating cellular constituent recycleing, cell development and differentiation. Autophagy is one of research hot spots in cytobiology at present, furthermore the relationship between autophagy and tumor is attracting great attention. Since Beth Levine ea al demonstrates that human cells that carry monoallelic deletions of the Beclin1/ATG6 gene are tumorigenic, autophagy has been considered as a tumor suppressor, and inducing autophagy is attempted to cancer therapy. But further investigations find that autophagy has dual role in cancer, in some circumstances, inducing autophagy may inhibit tumor cell growth, and result in autophagic cell death; but in most circumstances, autophagy may function as a cytoprotective mechanism by responsing to stress situations including hypoxia, low energy, oxidative stress and damaged mitochondria. Furthermore autophagy is tumor cell type- and stress dependent, that is, In different cell type or different stress mode, the role or function of autophagy changes. Myeloma cells are featured by exceedingly active protein metabolism such as synthesis and secretion of immunoglobulin, and as one of major protein metabolism pathways, what`s the function of autophagy in myeloma cells? There is no past experience at present. Based on the background above, in this study, by means of the model of myeloma cells (RPMI8226 and H929 and primary cells) , we try to explore the effects of autophagy on cell apoptosis induced by DOX and the correlateing mechanism.
Methods and Results: 1. In our work, MTT assays showed that autophagy inhibitor hydroxychloroquine (HCQ) could inhibit proliferation of RPMI8226 and H929 cells by dose-dependent manner in vitro. While autophagy inducer rapamycin had no effects on myeloma cell proliferation.2. Flow cytometer (FCM) displayed that autophagy inhibition by HCQ, 3-methlyadenine(3-MA) or bafilomycin A1 could enhance doxorubicin(DOX), cisplatin(DDP), mitoxantone(MIT), or melphalan(MEL) induced myeloma cell apoptosis repectively ( P < 0.05), while could not enhance vincristine(VCR), etoposide(VP-16) induced cell apoptosis(P>0.05).3. Autophagic morphology of myeloma cells was monitored by Electron microscopy and fluorescence microscopy.①By electron microscopy, it showed that the autophagosome amounts in untreated, 3-MA treated and 3-MA combined with DOX treated cells were scanty, moderate in HCQ ,BAF, or DOX singly treated cells, and abundent in HCQ or BAF combined with DOX treated cells, and also abundant in positive control: rapamycin treated cells.②LC3-FITC had been used to monitor autophagy by immunofluorescence. It showed that there are a high level of LC3 puncta in HCQ+DOX or BAF +DOX treated cells, and in rapamycin treated cells, moderate level in HCQ, BAF, or DOX singly treated cells, and low level in 3-MA+DOX, and there was diffuse fluorescence in untreated or 3-MA treated cells. 4. Western blot showed:①the amount of autophagic proteins Beclin1、Atg5、LC3-II increased gradually after RPMI8226 and H929 cells were treated with DOX for 0, 4, 8, 12h respectively, which indicated that autophagy was induced by DOX;②By means of analysis of express levels of Beclin1、Atg5、LC3-II after autophagy inhibitor HCQ, BAF or 3-MA combined with DOX, It showed that chemical sensitization of HCQ and BAF was due to post-sequestration step inhibition(by blocking fusion autophagosome with lysosome) to autophagy of myeloma cells, while 3-MA was due to sequestration inhibition.③Express levels of apoptosis protein caspase-3 and PARP treated by autophagy inhibitor HCQ, BAF or 3-MA combined with DOX increased compared with treated by DOX singly, which indicated that autophagy inhibition enhanced apoptosis induced by DOX. 5. The apoptosis induced by DOX also was enhanced by specific Beclin1 siRNA or Atg5 siRNA in H929 and RPMI8226 cells. 6. It was demonstrated in myeloma mouse model that in vivo autophagy inhibition also enhanced inhibition of tumor growth induced by DOX.
Conclusions: 1.Autophagy as a protective mechanism responses to the apoptosis induced by DOX . 2. Autophagy inhibition by chemical inhibitor or specific siRNA, could enhance the apoptosis induced by DOX in myeloma cell lines or primary cells; 3. In myeloma mouse models, autophagy inhibition also enhanced inhibition of tumor growth induced by DOX.
引文
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