苦马豆素诱导A549细胞和Eca-109细胞凋亡的信号转导通路研究
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摘要
苦马豆素（1，2，8-trihyroxyindolizidine，swainsonine，SW）是从豆科黄芪属（Astrgalus）和棘豆属（Oxytropis）植物中分离得到的一种吲哚兹定生物碱，能够在体内外抑制多种肿瘤细胞的生长，但其作用机制尚不清楚。许多化疗药物抑制肿瘤细胞生长是通过诱导肿瘤细胞凋亡来实现的，因此，研究肿瘤细胞凋亡信号转导通路，探索药物的抑瘤机制，已成为现代生物学研究的热点。本论文以人肺癌A549细胞和食管癌Eca-109细胞为研究对象，对SW在体外诱导细胞凋亡的情况和诱导凋亡的信号转导通路进行了研究，并复制了A549细胞Eca-109细胞裸鼠移植瘤模型，研究了SW在体内抑制肿瘤生长作用及机制。研究得到如下结果：
1. MTT检测结果显示，SW能够在体外剂量依赖性抑制人肺癌细胞系A549，Calu-3，H1299，SPC-A-1细胞和食管癌细胞系Eca-109，TE-1，TE-10细胞生长，且对肺癌细胞的生长抑制作用比对食管癌更强。表明SW对不同组织来源的肿瘤细胞的敏感性存在一定差异。
2.以A549细胞和Eca-109细胞为模型，对SW体外诱导细胞凋亡进行了研究。琼脂糖凝胶电泳显示，12μM的SW处理A549细胞24h或58μM的SW处理Eca-109细胞48h，基因组DNA被切断成180~200bp整数倍大小的片段；DAPI和AO/EB荧光染色显示，SW处理的细胞发生染色质凝聚、核固缩等凋亡特征性现象；电子显微镜观察到SW处理的细胞发生皱缩变圆、体积变小、表面微绒毛消失、核固缩、细胞内出现空泡、细胞膜内陷包裹细胞内容物形成凋亡小体的现象；Annexin V-FITC/PI双荧光染色流式细胞术检测显示，随着SW处理剂量的增加或处理时间的延长，细胞凋亡率逐渐升高，呈现出一定的剂量和时间依赖性关系，表明SW是通过诱导细胞凋亡抑制A549细胞和Eca-109细胞生长。
3.以12μM的SW处理A549细胞0~24h或58μM的SW处理Eca-109细胞0~48h，Caspase活性检测试验和Western blot检测结果均显示，SW处理能够时间依赖性激活Caspase-9和Caspase-3，而对Caspase-8的活性没有显著影响；广谱Caspase抑制剂，Caspase-9和Caspase-3的特异性抑制剂均能够抑制SW的凋亡诱导作用，显著降低细胞凋亡率，表明SW诱导的细胞凋亡依赖于Caspase-9/-3级联活化。SW处理对Fas，FasL的表达量没有明显影响，表明SW诱导的细胞凋亡不激活Fas/FasL/Caspase-8通路。Real-time qPCR和Western blot检测结果显示，SW处理能够上调促凋亡的Bax，下调抑制凋亡的Bcl-2，增加Bax/Bcl-2的比率，促进Bax从细胞浆向线粒体转位。JC-1染色、流式细胞术检测显示，随着Bax从细胞浆向线粒体转位，线粒体膜电位（mitochondrialmembrane potential，Δψm）去极化的细胞比率逐渐增加，提示SW是通过调节Bax和Bcl-2的表达影响线粒体的功能。进一步研究显示，线粒体中促凋亡分子细胞色素（ccytochromec，Cyt c）在SW作用下从线粒体释放到细胞浆中，在细胞浆中与凋亡蛋白酶激活因子1（apoptotic protease activating factor1，Apaf-1）和Caspase-9酶原结合为凋亡体（apoptosome），进而活化Caspase-9/-3级联反应，Caspase-3作为SW诱导细胞凋亡的主要执行分子对细胞内成分如多聚ADP核糖聚合酶（polyADP ribose polymerase，PARP等进行广泛降解，最终导致细胞凋亡。本研究未检测到线粒体第二激活因子（mitochondrial second mitochondrial-derived activator of caspase，Smac）和凋亡诱导因子（apoptosis inducing factor，AIF）伴随Cyt c释放出线粒体。SW处理具有野生型p53的A549细胞能够显著上调p53mRNA水平，明显增加p53蛋白含量，并在一定程度上促进p53蛋白磷酸化。但是，SW似乎并不能显著影响p53的转录活性。p53抑制剂pifithrin-α不能显著降低SW诱导的细胞凋亡率，表明在SW诱导的细胞凋亡过程中，p53可能不是以激活或抑制某些凋亡相关基因表达的方式发挥调控作用。
4.胸腺缺陷型BALB/c nu/nu裸小鼠接种A549细胞或Eca-109细胞，复制荷瘤小鼠模型，以剂量为1mg/kg/d和2.5mg/kg/d的SW灌胃治疗。在灌胃15d时开始观察到SW对A549细胞移植性肿瘤块生长的显著抑制作用，25d开始观察到对Eca-109细胞移植性肿瘤块生长的显著抑制作用。分别在灌胃15d和35d处死A549细胞荷瘤小鼠和Eca-109细胞荷瘤小鼠，取出肿瘤组织进行检测。结果发现，与对照组相比，灌胃SW能够显著降低移植性肿瘤块的湿重，表明SW能够抑制A549和Eca-109移植性肿瘤块在小鼠体内的生长速度。肿瘤组织学检测显示，SW治疗组移植性肿瘤组织变得较为疏松，部分肿瘤细胞核碎裂，组织间有一定量的巨噬细胞和中性粒细胞浸润，与对照组肿瘤组织细胞旺盛生长的状态有明显的差异。TUNEL染色检查发现，SW治疗组肿瘤组织均出现TUNEL阳性染色的凋亡细胞，且凋亡细胞数目随SW灌胃剂量加大而增多，表明SW也能在体内诱导肿瘤细胞凋亡。免疫组织化学染色和Western blot检测结果均显示，灌胃SW可上调移植性肿瘤中Bax、下调Bcl-2的表达，同时促进Bax和Cyt c在移植性肿瘤细胞胞浆与线粒体之间的互相转位，表明线粒体通路在SW体内诱导细胞凋亡过程中被激活，提示SW在体内和体外诱导细胞肿瘤凋亡的机制一致。对SW灌胃的荷瘤小鼠主要脏器进行病理学观察的结果表明，SW对小鼠小脑、心、肺、脾等不产生明显的组织病理学变化，但高剂量SW能够引起肝和肾发生轻微组织病理学变化。
本论文首次阐明SW是通过激活细胞线粒体信号转导通路诱导A549细胞和Eca-109细胞发生凋亡，从而抑制其在体内外生长。研究结果将为进一步揭示SW的抑瘤机理和研发SW成为肿瘤治疗药物奠定基础。
Swainsonine (1,2,8-trihyroxyindolizidine, SW), an indolizidine alkaloid isolated fromAstragalus and Oxytropis species (Leguminosae), can inhibit the growth of several cancercells in vitro and in vivo. However, the mechanisms are not clear. A lot of chemotherapy drugsplay their anti-tumor activities through induction of apoptosis. Thus, the investigation ofapoptotic signal pathways and the mechanisms of anti-tumor drugs became a hot topic incurrent biological research. In this study, we employed human lung cancer549cells andesophageal carcinoma Eca-109cells to evaluate the effects of SW on the cell growth andinvestigate the possible mechanisms involved in. Congenital athymic BABL/c nude (nu/nu)mice xenografted with A549cells and Eca-109cells were also used to investigate the in vivoanti-tumor activity of SW. From the experiments, the following results were obtained:
1. MTT assay showed that SW treatment concentration-dependently inhibited the growthof human lung cancer cell lines A549, Calu-3, H1299, SPC-A-1and esophageal carcinomacell lines Eca-109, TE-1and TE-10, and that lung cancer cells were more sensitive to SWtreatment than that of esophageal carcinoma cells, which suggested that carcinoma cellsderived from different tissues exhibit different sensitivity to SW treatment.
2. The apoptotic induction effects of SW on A549and Eca-109cell models wereevaluated. Evident DNA ladder were observed from agarose gel electrophoresis the whenA549and Eca-109cells were treated with12μM and58μM for24and48h, respectively.DAPI and AO/EB staining showed characteristically morphological changes of apoptosis inSW treated cells such as chromatin condensation, nuclear fragmentation.Transmission andscanning electron microscope observation showed that the cells shrinkaged, reduced involume with microvilli disappearance, chromatin condensation, nuclear fragmentation, andformation of membrane embedded apoptotic bodies after SW treatment. Flow cytometryassay showed that that SW treatment induced cell apoptosis in a concentration-andtime-dependent manner. These results demonstrated that SW inhibited the growth of A549cells and Eca-109cells through induction of apoptosis.
3. A549and Eca-109cells were treated with12μM and58μM for0~24h and0~48h，respectively. Results from caspase activity analysis and Western blot assay showed that SW treatment time-dependently increased the activities of caspase-9and caspase-3, while notaffected that of caspase-8. Pan-caspase inhibitors, caspase-9specific inhibitor and caspase-3specific inhibitor could significantly prevented the SW-induced apoptotic effects, suggestedSW-induced apoptosis dependent on the activation of caspase-9/-3cascade. SW treatment didnot affect the expression of Fas and FasL, suggested Fas/FasL/caspase-8signal pathway maynot be involved in the process of SW-induced apoptosis. Both Real-time qPCR and Westernblot assay showed that SW treatment up-regulated Bax, down-regulated Bcl-2, increased theBax/Bcl-2ratio, and promoted the translocation of Bax from cytosol to mitochondira.Consistant with this, JC-1staining showed that the percentage of Δψm-depolarized cells weresignificantly increased, suggesting that SW treatment destruced the mitochondrial intergritythrough regulating Bax and Bcl-2expression. Further study showed SW treatment promotedthe release of cytochrome c (Cyt c) from mitochondira to cytosol, where it binded to apoptoticprotease activating factor1(Apaf-1) and pro-caspase-9to form apoptosome, which in turnactivated caspase-9, followed by the activation of caspase-3. Caspase-3, the main executer ofapoptosis, degraded the cellular contents such as poly ADP ribose polymerase (PARP),resulting apoptosis. In this study, we did not observe the release of Smac and AIF frommitochondria in SW-treated cells. SW treatment significantly increased the p53mRNA levelsand p53protein accumulation, and promoted the phosphorylation of p53. However, it seemedthat SW treatment could not affect the transcriptional activity of p53. On the other hand, thep53inhibitor pifithrin-α did not show any attenuated effects on SW-induced apoptotic rate,suggesting that p53may not play a role through activating or inactivating some apoptoticrelated genes in the process SW-induced apoptosis.
4. Congenital athymic BABL/c nude (nu/nu) mice were xenografted with A549cells orEca-109cells, and the xenografted mice were administrated1mg/kg/d or2.5mg/kg/d does ofSW respectively. Significant growth inhibition of A549xenograft tumors and Eca-109xenograft tumors began to be observed after15d and25d. Mice were executed at15d or35d after and A549xenograft tumors or Eca-109xenograft tumors were collected, respectively,for further study. The results showed that the wet weight of A549xenograft tumors andEca-109xenograft tumors significantly decreased in mice received SW compared to thecontrol, suggesting that SW intake could inhibit the growth of xenograft tumors in vivo.Histological observation on the xenograft tumors showed that some of the tumor cellsappeared nuclear fragmentation, and that numerous inflammatory cells such as macrophages,neutrophils were infiltrated into tissues of SW-treated groups, compared with cells that arethriving in control groups. TUNEL assay showed evident in situ apoptosis in xenograft tumorsections at1and2.5mg/kg/day of SW-treated groups, but not in the sections of control group. The percentage of apoptotic cells were increased with the increasing dose of SW received.Results obtained from immunohistochemical staining and Western blot assay showed thatSW-intake up-regulated Bax, down-regulated Bcl-2, promoted the redistribution of Bax andCyt c in xenograft tumor cells, which implied the activation of mitochondria-mediatedapoptotic pathways, suggesting that SW utilized similar mechanisms to induce tumor cellapoptosis in vitro and in vivo. Observation of the brains and internal organs from SW-treatedmice did not show evident pathological changes in cerebellum, heart, lung and spleen.However, high dose of SW may exhibit potential liver toxicity and kidney toxicity.
Taken together, this study illustrated that SW induced A549cells and Eca-109cellsapoptosis throuth activation of mitochondrial pathway, whereby inhibiting the growth of thetumor cells in vitro and in vivo. This study will lay the foundations for further revealing themechanisms of SW anti-tumor and developing SW to be a new anti-tumor drugs.
1. MTT检测结果显示，SW能够在体外剂量依赖性抑制人肺癌细胞系A549，Calu-3，H1299，SPC-A-1细胞和食管癌细胞系Eca-109，TE-1，TE-10细胞生长，且对肺癌细胞的生长抑制作用比对食管癌更强。表明SW对不同组织来源的肿瘤细胞的敏感性存在一定差异。
2.以A549细胞和Eca-109细胞为模型，对SW体外诱导细胞凋亡进行了研究。琼脂糖凝胶电泳显示，12μM的SW处理A549细胞24h或58μM的SW处理Eca-109细胞48h，基因组DNA被切断成180~200bp整数倍大小的片段；DAPI和AO/EB荧光染色显示，SW处理的细胞发生染色质凝聚、核固缩等凋亡特征性现象；电子显微镜观察到SW处理的细胞发生皱缩变圆、体积变小、表面微绒毛消失、核固缩、细胞内出现空泡、细胞膜内陷包裹细胞内容物形成凋亡小体的现象；Annexin V-FITC/PI双荧光染色流式细胞术检测显示，随着SW处理剂量的增加或处理时间的延长，细胞凋亡率逐渐升高，呈现出一定的剂量和时间依赖性关系，表明SW是通过诱导细胞凋亡抑制A549细胞和Eca-109细胞生长。
3.以12μM的SW处理A549细胞0~24h或58μM的SW处理Eca-109细胞0~48h，Caspase活性检测试验和Western blot检测结果均显示，SW处理能够时间依赖性激活Caspase-9和Caspase-3，而对Caspase-8的活性没有显著影响；广谱Caspase抑制剂，Caspase-9和Caspase-3的特异性抑制剂均能够抑制SW的凋亡诱导作用，显著降低细胞凋亡率，表明SW诱导的细胞凋亡依赖于Caspase-9/-3级联活化。SW处理对Fas，FasL的表达量没有明显影响，表明SW诱导的细胞凋亡不激活Fas/FasL/Caspase-8通路。Real-time qPCR和Western blot检测结果显示，SW处理能够上调促凋亡的Bax，下调抑制凋亡的Bcl-2，增加Bax/Bcl-2的比率，促进Bax从细胞浆向线粒体转位。JC-1染色、流式细胞术检测显示，随着Bax从细胞浆向线粒体转位，线粒体膜电位（mitochondrialmembrane potential，Δψm）去极化的细胞比率逐渐增加，提示SW是通过调节Bax和Bcl-2的表达影响线粒体的功能。进一步研究显示，线粒体中促凋亡分子细胞色素（ccytochromec，Cyt c）在SW作用下从线粒体释放到细胞浆中，在细胞浆中与凋亡蛋白酶激活因子1（apoptotic protease activating factor1，Apaf-1）和Caspase-9酶原结合为凋亡体（apoptosome），进而活化Caspase-9/-3级联反应，Caspase-3作为SW诱导细胞凋亡的主要执行分子对细胞内成分如多聚ADP核糖聚合酶（polyADP ribose polymerase，PARP等进行广泛降解，最终导致细胞凋亡。本研究未检测到线粒体第二激活因子（mitochondrial second mitochondrial-derived activator of caspase，Smac）和凋亡诱导因子（apoptosis inducing factor，AIF）伴随Cyt c释放出线粒体。SW处理具有野生型p53的A549细胞能够显著上调p53mRNA水平，明显增加p53蛋白含量，并在一定程度上促进p53蛋白磷酸化。但是，SW似乎并不能显著影响p53的转录活性。p53抑制剂pifithrin-α不能显著降低SW诱导的细胞凋亡率，表明在SW诱导的细胞凋亡过程中，p53可能不是以激活或抑制某些凋亡相关基因表达的方式发挥调控作用。
4.胸腺缺陷型BALB/c nu/nu裸小鼠接种A549细胞或Eca-109细胞，复制荷瘤小鼠模型，以剂量为1mg/kg/d和2.5mg/kg/d的SW灌胃治疗。在灌胃15d时开始观察到SW对A549细胞移植性肿瘤块生长的显著抑制作用，25d开始观察到对Eca-109细胞移植性肿瘤块生长的显著抑制作用。分别在灌胃15d和35d处死A549细胞荷瘤小鼠和Eca-109细胞荷瘤小鼠，取出肿瘤组织进行检测。结果发现，与对照组相比，灌胃SW能够显著降低移植性肿瘤块的湿重，表明SW能够抑制A549和Eca-109移植性肿瘤块在小鼠体内的生长速度。肿瘤组织学检测显示，SW治疗组移植性肿瘤组织变得较为疏松，部分肿瘤细胞核碎裂，组织间有一定量的巨噬细胞和中性粒细胞浸润，与对照组肿瘤组织细胞旺盛生长的状态有明显的差异。TUNEL染色检查发现，SW治疗组肿瘤组织均出现TUNEL阳性染色的凋亡细胞，且凋亡细胞数目随SW灌胃剂量加大而增多，表明SW也能在体内诱导肿瘤细胞凋亡。免疫组织化学染色和Western blot检测结果均显示，灌胃SW可上调移植性肿瘤中Bax、下调Bcl-2的表达，同时促进Bax和Cyt c在移植性肿瘤细胞胞浆与线粒体之间的互相转位，表明线粒体通路在SW体内诱导细胞凋亡过程中被激活，提示SW在体内和体外诱导细胞肿瘤凋亡的机制一致。对SW灌胃的荷瘤小鼠主要脏器进行病理学观察的结果表明，SW对小鼠小脑、心、肺、脾等不产生明显的组织病理学变化，但高剂量SW能够引起肝和肾发生轻微组织病理学变化。
本论文首次阐明SW是通过激活细胞线粒体信号转导通路诱导A549细胞和Eca-109细胞发生凋亡，从而抑制其在体内外生长。研究结果将为进一步揭示SW的抑瘤机理和研发SW成为肿瘤治疗药物奠定基础。
Swainsonine (1,2,8-trihyroxyindolizidine, SW), an indolizidine alkaloid isolated fromAstragalus and Oxytropis species (Leguminosae), can inhibit the growth of several cancercells in vitro and in vivo. However, the mechanisms are not clear. A lot of chemotherapy drugsplay their anti-tumor activities through induction of apoptosis. Thus, the investigation ofapoptotic signal pathways and the mechanisms of anti-tumor drugs became a hot topic incurrent biological research. In this study, we employed human lung cancer549cells andesophageal carcinoma Eca-109cells to evaluate the effects of SW on the cell growth andinvestigate the possible mechanisms involved in. Congenital athymic BABL/c nude (nu/nu)mice xenografted with A549cells and Eca-109cells were also used to investigate the in vivoanti-tumor activity of SW. From the experiments, the following results were obtained:
1. MTT assay showed that SW treatment concentration-dependently inhibited the growthof human lung cancer cell lines A549, Calu-3, H1299, SPC-A-1and esophageal carcinomacell lines Eca-109, TE-1and TE-10, and that lung cancer cells were more sensitive to SWtreatment than that of esophageal carcinoma cells, which suggested that carcinoma cellsderived from different tissues exhibit different sensitivity to SW treatment.
2. The apoptotic induction effects of SW on A549and Eca-109cell models wereevaluated. Evident DNA ladder were observed from agarose gel electrophoresis the whenA549and Eca-109cells were treated with12μM and58μM for24and48h, respectively.DAPI and AO/EB staining showed characteristically morphological changes of apoptosis inSW treated cells such as chromatin condensation, nuclear fragmentation.Transmission andscanning electron microscope observation showed that the cells shrinkaged, reduced involume with microvilli disappearance, chromatin condensation, nuclear fragmentation, andformation of membrane embedded apoptotic bodies after SW treatment. Flow cytometryassay showed that that SW treatment induced cell apoptosis in a concentration-andtime-dependent manner. These results demonstrated that SW inhibited the growth of A549cells and Eca-109cells through induction of apoptosis.
3. A549and Eca-109cells were treated with12μM and58μM for0~24h and0~48h，respectively. Results from caspase activity analysis and Western blot assay showed that SW treatment time-dependently increased the activities of caspase-9and caspase-3, while notaffected that of caspase-8. Pan-caspase inhibitors, caspase-9specific inhibitor and caspase-3specific inhibitor could significantly prevented the SW-induced apoptotic effects, suggestedSW-induced apoptosis dependent on the activation of caspase-9/-3cascade. SW treatment didnot affect the expression of Fas and FasL, suggested Fas/FasL/caspase-8signal pathway maynot be involved in the process of SW-induced apoptosis. Both Real-time qPCR and Westernblot assay showed that SW treatment up-regulated Bax, down-regulated Bcl-2, increased theBax/Bcl-2ratio, and promoted the translocation of Bax from cytosol to mitochondira.Consistant with this, JC-1staining showed that the percentage of Δψm-depolarized cells weresignificantly increased, suggesting that SW treatment destruced the mitochondrial intergritythrough regulating Bax and Bcl-2expression. Further study showed SW treatment promotedthe release of cytochrome c (Cyt c) from mitochondira to cytosol, where it binded to apoptoticprotease activating factor1(Apaf-1) and pro-caspase-9to form apoptosome, which in turnactivated caspase-9, followed by the activation of caspase-3. Caspase-3, the main executer ofapoptosis, degraded the cellular contents such as poly ADP ribose polymerase (PARP),resulting apoptosis. In this study, we did not observe the release of Smac and AIF frommitochondria in SW-treated cells. SW treatment significantly increased the p53mRNA levelsand p53protein accumulation, and promoted the phosphorylation of p53. However, it seemedthat SW treatment could not affect the transcriptional activity of p53. On the other hand, thep53inhibitor pifithrin-α did not show any attenuated effects on SW-induced apoptotic rate,suggesting that p53may not play a role through activating or inactivating some apoptoticrelated genes in the process SW-induced apoptosis.
4. Congenital athymic BABL/c nude (nu/nu) mice were xenografted with A549cells orEca-109cells, and the xenografted mice were administrated1mg/kg/d or2.5mg/kg/d does ofSW respectively. Significant growth inhibition of A549xenograft tumors and Eca-109xenograft tumors began to be observed after15d and25d. Mice were executed at15d or35d after and A549xenograft tumors or Eca-109xenograft tumors were collected, respectively,for further study. The results showed that the wet weight of A549xenograft tumors andEca-109xenograft tumors significantly decreased in mice received SW compared to thecontrol, suggesting that SW intake could inhibit the growth of xenograft tumors in vivo.Histological observation on the xenograft tumors showed that some of the tumor cellsappeared nuclear fragmentation, and that numerous inflammatory cells such as macrophages,neutrophils were infiltrated into tissues of SW-treated groups, compared with cells that arethriving in control groups. TUNEL assay showed evident in situ apoptosis in xenograft tumorsections at1and2.5mg/kg/day of SW-treated groups, but not in the sections of control group. The percentage of apoptotic cells were increased with the increasing dose of SW received.Results obtained from immunohistochemical staining and Western blot assay showed thatSW-intake up-regulated Bax, down-regulated Bcl-2, promoted the redistribution of Bax andCyt c in xenograft tumor cells, which implied the activation of mitochondria-mediatedapoptotic pathways, suggesting that SW utilized similar mechanisms to induce tumor cellapoptosis in vitro and in vivo. Observation of the brains and internal organs from SW-treatedmice did not show evident pathological changes in cerebellum, heart, lung and spleen.However, high dose of SW may exhibit potential liver toxicity and kidney toxicity.
Taken together, this study illustrated that SW induced A549cells and Eca-109cellsapoptosis throuth activation of mitochondrial pathway, whereby inhibiting the growth of thetumor cells in vitro and in vivo. This study will lay the foundations for further revealing themechanisms of SW anti-tumor and developing SW to be a new anti-tumor drugs.
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