姜黄素影响HT-29结肠癌细胞生长、增殖的分子机制研究
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摘要
姜黄素是从天然植物—姜黄根茎中提取的一种多酚,具有抗氧化、消炎、抗肿瘤、预防老年性痴呆、治疗风湿等多种功效。本论文旨在研究姜黄素对HT-29结肠癌细胞生长、增殖及细胞存活率的影响,并在分子水平上研究姜黄素对HT-29细胞线粒体凋亡途径、β-catenin/Tcf-4信号途径活性的影响,从而探讨姜黄素抑制细胞生长、增殖的分子机制。
本论文首先用倒置显微镜观察了10-80μM姜黄素处理对HT-29细胞生长的影响,结果发现姜黄素处理能够显著抑制细胞的生长。用Hoechst 33258荧光染料染色也发现,姜黄素能够诱导HT-29细胞核浓缩,诱导细胞凋亡。对HT-29细胞线粒体膜电位及caspase-3活性的测定表明,10-80μM的姜黄素可以导致线粒体膜电位显著下降(P＜0.05),caspase-3的活性显著提高(P＜0.05)。
为了研究姜黄素抑制HT-29细胞生长增殖,诱导其死亡的分子机理,本研究运用RT-PCR技术研究了细胞线粒体凋亡途径相关蛋白mRNA的水平,结果表明,用高于40μM的姜黄素处理HT-29细胞,能够显著降低细胞中抗凋亡蛋白Bcl-2、Bcl-XL、survivin mRNA的水平(P＜0.05),促凋亡蛋白Bax mRNA的水平会显著升高(P＜0.05),caspase-3 mRNA的水平则没有显著变化。Western-blotting结果则表明,10-80μM的姜黄素可以导致细胞中促凋亡蛋白Bad与Bax的水平显著升高,凋亡抑制蛋白Bcl-2、Bcl-xL及survivin的水平则明显下降;40μM以上的姜黄素处理HT-29细胞,可以激活其caspase-3,诱导PARP降解;Western-blotting结果还表明,10μM以上的姜黄素可以导致HT-29细胞线粒体细胞色素c的释放。以上结果表明,姜黄素可能通过线粒体途径诱导HT-29细胞凋亡。
β-catenin/Tcf-4信号途径在大多数结肠癌细胞中异常激活,该通路可以激活多种原癌基因的表达,促进结肠癌细胞株生长、分化,为了研究姜黄素是否通过影响该信号途径的活性,抑制肿瘤细胞生长、分化,并可能诱导其凋亡。本论文用Western-blotting技术研究了姜黄素对细胞内β-catenin水平的影响,结果发现,姜黄素能够导致HT-29细胞内β-catenin裂解,从而降低细胞总β-catenin的水平,接着我们将免疫共沉淀技术(IP)和western-blotting技术相结合,研究了姜黄素对细胞核内β-catenin/Tcf-4复合物水平的影响,结果发现,姜黄素可以降低核内β-catenin/Tcf-4复合物的水平。此外,RT-PCR结果也表明,姜黄素处理能够显著降低β-catenin/Tcf-4的靶基因c-myc与cyclinD1 mRNA及蛋白质的水平(P＜0.05),这说明姜黄能够下调β-catenin/Tcf-4的转录激活活性。用caspase-3的特异性小分子抑制剂Z-DEVD-FMK预处理HT-29细胞,则发现姜黄素诱导的β-catenin断裂被抑制;而β-catenin/Tcf-4下游靶基因的表达则不受Z-DEVD-FMK处理的影响,这说明,姜黄素诱导的HT-29细胞内β-catenin断裂是由caspase-3介导的,姜黄素诱导的β-catenin/Tcf-4转录激活能力下降则与caspase-3无关。
本论文运用RT-PCR及western-blotting技术进一步研究了β-catenin/Tcf-4转录激活的靶基因PPARδ、VEGF、COX-2、14-3-3ε等的表达情况,结果表明,40-80μM的姜黄素处理可以显著下调靶基因PPARδmRNA及蛋白质的水平(P＜0.05),受PPARδ调节的基因14-3-3ε的表达水平也显著下降(P＜0.05),而14-3-3ε在细胞中可以与促凋亡蛋白Bad结合,从而抑制凋亡,姜黄素下调14-3-3ε的水平可能与Bad的水平升高有关。同时,研究还发现,姜黄素处理可以显著下调β-catenin/Tcf-4信号路径VEGF和COX-2二个靶基因的水平,VEGF及COX-2均与结肠癌细胞的增殖、分化及血管形成密切相关,这进一步说明了姜黄素可能通过下调β-catenin/Tcf-4信号途径活性,来抑制结肠癌肿瘤细胞的生长与增殖。
为了进一步研究姜黄素抑制HT-29细胞生长、增殖的分子机制,本论文研究了姜黄素的抗氧化及对HT-29细胞内活性氧水平的影响。用化学体系进行的实验证明,姜黄素可以猝灭DPPH、ABTS~(·+)、O2~(·-)、·OH等自由基,抑制亚油酸的过氧化反应,保护pBR322质粒DNA免受羟自由基的氧化损伤。用10-80μM姜黄素处理HT-29细胞后,我们测定了细胞内活性氧(ROS)及谷胱甘肽的水平,结果发现,姜黄素处理可以显著提高HT-29细胞内活性氧的水平,并激活caspase-3,下调Bcl-2的表达水平,诱导HT-29细胞凋亡(P＜0.05)。为研究姜黄素诱导的caspase-3激活及细胞凋亡是否与其刺激的胞内活性氧水平升高有关,本研究用抗氧化剂N-乙酰半胱氨酸(NAC)和过氧化氢酶(catalase)处理,以消除自由基,结果发现,NAC和catalase处理后,姜黄素不能诱导caspase-3激活,姜黄素处理导致的细胞存活率下降也被抑制。
本论文研究表明,姜黄素可能是通过刺激HT-29细胞产生高水平的活性氧,激活caspase-3,从而激活HT-29细胞线粒体凋亡途径;姜黄素还可以通过不依赖于caspase-3方式,下调β-catenin/Tcf-4信号活性,抑制其下游靶基因的表达,从而抑制HT-29结肠癌细胞的生长、增殖。
Curcumin is an important polyphenol extracted from the rhizomes of Curcuma longa L.Several studies have shown curcumin exerts antioxidant,anti-inflammatory, anti-carcinogenic,Alzheimer's preventional and antiarthritic activities.This study will focus on the molecular mechanisms of the effects of curcumin on the growth and proliferation of HT-29 cells.
In this study,we observed treatment with 10-80μM curucmin inhibited the growth of HT-29 cells by microscopic wounding assay.Hoechst 33258 staining showed that curcumin significantly induced apoptosis of HT-29 cells.Exposure to 10-80μM curucmin also markedly induced the mitochondrial membrane potential(ΔΨm) collapse and activation of caspase-3(P＜0.05).
To investigate the mechanisms of curcumin induced apoptosis of HT-29 cells,the release of cytochrome c from the mitochondria and the apoptosis-related proteins such as Bax,Bcl-2,Bcl-xL,Bad,caspase-3,PARP,and survivin were determined by western blotting analysis and their mRNA expressions were assayed by reverse transcriptase-polymerase chain reaction(RT-PCR).A significant decrease in expression of the anti-apoptotic protein such as Bcl-2,Bcl-xL and survivin was observed after exposure to 10-80μM curcumin(P＜0.05),while the levels of pro-apoptotic protein such as Bax and Bad increased in the curcumin-treated cells (P＜0.05).Curcumin also induced the release of cytochrome c,the activation of caspase-3,and the cleavage of PARP in a dose-dependent manner(P＜0.05).These data suggested that curcumin induced the HT-29 cell apoptosis possibly was via the mitochondria mediated pathway.
Irregular activation ofβ-catenin/Tcf-4 signaling pathway occurs in many colorectal cancer cells.We studied the effects of curcumin on the level ofβ-catenin in HT-29 cells by western-blotting.The results showed that incubation with 20-80μM curcumin could induce cleavage ofβ-catenin.The level ofβ-catenin/Tcf-4 complex in HT-29 cell nucleus was studied by co-immunoprecipitation and western blotting.The expression of the target genes such as c-myc and cyclinD1 was investigated by RT-PCR and western blotting.The results showed that the association ofβ-catenin with Tcf-4 in nucleus could be inhibited by curcumin(P＜0.05).The expression of c-myc and cyclinD1 was also downregulated by curcumin.Pretreatement of HT-29 cells with Z-DEVD-FMK,a specific inhibitor of caspase-3,could inhibit the curcumin induced cleavage ofβ-catenin.However,curcumin induced downregulation of c-myc and cyclinD1 could not be blocked by Z-DEVD-FMK.These results suggested curcumin could induce the cleavage ofβ-catenin by activition of caspases and downregulate the activity ofβ-catenin/Tcf signaling pathway independent of the caspases in HT-29 cells.
We also studied the expression of the target genes ofβ-catenin/Tcf-4 signaling pathway such as PPARδ,VEGF,COX-2 and 14-3-3εin HT-29 cells.The results showed that curcumin treatment decreased the expression of PPARδ,VEGF,COX-2 and 14-3-3ε(P＜0.05).In cytoplasm,14-3-3εcan associate with the pro-apoptotic protein,Bad,and inhibit the pro-apoptotic activity of Bad.Our results showed curcumin might increase the level of Bad by down-regulation of 14-3-3εin HT-29 cells.
To investigate the molecular mechanism of curcumin induced HT-29 cell death and growth inhibiton,we studied the anti-oxidant and pro-oxidant activities of curcumin. The in vitro assay showed curcumin had an effective DPPH~·scavenging,ABTS~+ scavenging,superoxide anion radical scavenging,hydroxyl free radical scavenging, ferric ions(Fe~(3+)) reducing power activities.Curcumin could also inhibit the peroxidation of linoleic acid and the oxidative damage of pBR322 DNA induced by hydroxyl free radical.The in vivo assay showed curcumin could increase the levels of the reactive oxygen species(ROS) and glutathion in HT-29 cells(P＜0.05). N-acetylcysteine(NAC) and catalase pretreatment could significantly inhibit curucmin induced increase of ROS and caspase-3 activation(P＜0.05),which indicated curcumin indcued HT-29 cell apoptosis might be mediated by the stimulated increase of ROS.
本论文首先用倒置显微镜观察了10-80μM姜黄素处理对HT-29细胞生长的影响,结果发现姜黄素处理能够显著抑制细胞的生长。用Hoechst 33258荧光染料染色也发现,姜黄素能够诱导HT-29细胞核浓缩,诱导细胞凋亡。对HT-29细胞线粒体膜电位及caspase-3活性的测定表明,10-80μM的姜黄素可以导致线粒体膜电位显著下降(P＜0.05),caspase-3的活性显著提高(P＜0.05)。
为了研究姜黄素抑制HT-29细胞生长增殖,诱导其死亡的分子机理,本研究运用RT-PCR技术研究了细胞线粒体凋亡途径相关蛋白mRNA的水平,结果表明,用高于40μM的姜黄素处理HT-29细胞,能够显著降低细胞中抗凋亡蛋白Bcl-2、Bcl-XL、survivin mRNA的水平(P＜0.05),促凋亡蛋白Bax mRNA的水平会显著升高(P＜0.05),caspase-3 mRNA的水平则没有显著变化。Western-blotting结果则表明,10-80μM的姜黄素可以导致细胞中促凋亡蛋白Bad与Bax的水平显著升高,凋亡抑制蛋白Bcl-2、Bcl-xL及survivin的水平则明显下降;40μM以上的姜黄素处理HT-29细胞,可以激活其caspase-3,诱导PARP降解;Western-blotting结果还表明,10μM以上的姜黄素可以导致HT-29细胞线粒体细胞色素c的释放。以上结果表明,姜黄素可能通过线粒体途径诱导HT-29细胞凋亡。
β-catenin/Tcf-4信号途径在大多数结肠癌细胞中异常激活,该通路可以激活多种原癌基因的表达,促进结肠癌细胞株生长、分化,为了研究姜黄素是否通过影响该信号途径的活性,抑制肿瘤细胞生长、分化,并可能诱导其凋亡。本论文用Western-blotting技术研究了姜黄素对细胞内β-catenin水平的影响,结果发现,姜黄素能够导致HT-29细胞内β-catenin裂解,从而降低细胞总β-catenin的水平,接着我们将免疫共沉淀技术(IP)和western-blotting技术相结合,研究了姜黄素对细胞核内β-catenin/Tcf-4复合物水平的影响,结果发现,姜黄素可以降低核内β-catenin/Tcf-4复合物的水平。此外,RT-PCR结果也表明,姜黄素处理能够显著降低β-catenin/Tcf-4的靶基因c-myc与cyclinD1 mRNA及蛋白质的水平(P＜0.05),这说明姜黄能够下调β-catenin/Tcf-4的转录激活活性。用caspase-3的特异性小分子抑制剂Z-DEVD-FMK预处理HT-29细胞,则发现姜黄素诱导的β-catenin断裂被抑制;而β-catenin/Tcf-4下游靶基因的表达则不受Z-DEVD-FMK处理的影响,这说明,姜黄素诱导的HT-29细胞内β-catenin断裂是由caspase-3介导的,姜黄素诱导的β-catenin/Tcf-4转录激活能力下降则与caspase-3无关。
本论文运用RT-PCR及western-blotting技术进一步研究了β-catenin/Tcf-4转录激活的靶基因PPARδ、VEGF、COX-2、14-3-3ε等的表达情况,结果表明,40-80μM的姜黄素处理可以显著下调靶基因PPARδmRNA及蛋白质的水平(P＜0.05),受PPARδ调节的基因14-3-3ε的表达水平也显著下降(P＜0.05),而14-3-3ε在细胞中可以与促凋亡蛋白Bad结合,从而抑制凋亡,姜黄素下调14-3-3ε的水平可能与Bad的水平升高有关。同时,研究还发现,姜黄素处理可以显著下调β-catenin/Tcf-4信号路径VEGF和COX-2二个靶基因的水平,VEGF及COX-2均与结肠癌细胞的增殖、分化及血管形成密切相关,这进一步说明了姜黄素可能通过下调β-catenin/Tcf-4信号途径活性,来抑制结肠癌肿瘤细胞的生长与增殖。
为了进一步研究姜黄素抑制HT-29细胞生长、增殖的分子机制,本论文研究了姜黄素的抗氧化及对HT-29细胞内活性氧水平的影响。用化学体系进行的实验证明,姜黄素可以猝灭DPPH、ABTS~(·+)、O2~(·-)、·OH等自由基,抑制亚油酸的过氧化反应,保护pBR322质粒DNA免受羟自由基的氧化损伤。用10-80μM姜黄素处理HT-29细胞后,我们测定了细胞内活性氧(ROS)及谷胱甘肽的水平,结果发现,姜黄素处理可以显著提高HT-29细胞内活性氧的水平,并激活caspase-3,下调Bcl-2的表达水平,诱导HT-29细胞凋亡(P＜0.05)。为研究姜黄素诱导的caspase-3激活及细胞凋亡是否与其刺激的胞内活性氧水平升高有关,本研究用抗氧化剂N-乙酰半胱氨酸(NAC)和过氧化氢酶(catalase)处理,以消除自由基,结果发现,NAC和catalase处理后,姜黄素不能诱导caspase-3激活,姜黄素处理导致的细胞存活率下降也被抑制。
本论文研究表明,姜黄素可能是通过刺激HT-29细胞产生高水平的活性氧,激活caspase-3,从而激活HT-29细胞线粒体凋亡途径;姜黄素还可以通过不依赖于caspase-3方式,下调β-catenin/Tcf-4信号活性,抑制其下游靶基因的表达,从而抑制HT-29结肠癌细胞的生长、增殖。
Curcumin is an important polyphenol extracted from the rhizomes of Curcuma longa L.Several studies have shown curcumin exerts antioxidant,anti-inflammatory, anti-carcinogenic,Alzheimer's preventional and antiarthritic activities.This study will focus on the molecular mechanisms of the effects of curcumin on the growth and proliferation of HT-29 cells.
In this study,we observed treatment with 10-80μM curucmin inhibited the growth of HT-29 cells by microscopic wounding assay.Hoechst 33258 staining showed that curcumin significantly induced apoptosis of HT-29 cells.Exposure to 10-80μM curucmin also markedly induced the mitochondrial membrane potential(ΔΨm) collapse and activation of caspase-3(P＜0.05).
To investigate the mechanisms of curcumin induced apoptosis of HT-29 cells,the release of cytochrome c from the mitochondria and the apoptosis-related proteins such as Bax,Bcl-2,Bcl-xL,Bad,caspase-3,PARP,and survivin were determined by western blotting analysis and their mRNA expressions were assayed by reverse transcriptase-polymerase chain reaction(RT-PCR).A significant decrease in expression of the anti-apoptotic protein such as Bcl-2,Bcl-xL and survivin was observed after exposure to 10-80μM curcumin(P＜0.05),while the levels of pro-apoptotic protein such as Bax and Bad increased in the curcumin-treated cells (P＜0.05).Curcumin also induced the release of cytochrome c,the activation of caspase-3,and the cleavage of PARP in a dose-dependent manner(P＜0.05).These data suggested that curcumin induced the HT-29 cell apoptosis possibly was via the mitochondria mediated pathway.
Irregular activation ofβ-catenin/Tcf-4 signaling pathway occurs in many colorectal cancer cells.We studied the effects of curcumin on the level ofβ-catenin in HT-29 cells by western-blotting.The results showed that incubation with 20-80μM curcumin could induce cleavage ofβ-catenin.The level ofβ-catenin/Tcf-4 complex in HT-29 cell nucleus was studied by co-immunoprecipitation and western blotting.The expression of the target genes such as c-myc and cyclinD1 was investigated by RT-PCR and western blotting.The results showed that the association ofβ-catenin with Tcf-4 in nucleus could be inhibited by curcumin(P＜0.05).The expression of c-myc and cyclinD1 was also downregulated by curcumin.Pretreatement of HT-29 cells with Z-DEVD-FMK,a specific inhibitor of caspase-3,could inhibit the curcumin induced cleavage ofβ-catenin.However,curcumin induced downregulation of c-myc and cyclinD1 could not be blocked by Z-DEVD-FMK.These results suggested curcumin could induce the cleavage ofβ-catenin by activition of caspases and downregulate the activity ofβ-catenin/Tcf signaling pathway independent of the caspases in HT-29 cells.
We also studied the expression of the target genes ofβ-catenin/Tcf-4 signaling pathway such as PPARδ,VEGF,COX-2 and 14-3-3εin HT-29 cells.The results showed that curcumin treatment decreased the expression of PPARδ,VEGF,COX-2 and 14-3-3ε(P＜0.05).In cytoplasm,14-3-3εcan associate with the pro-apoptotic protein,Bad,and inhibit the pro-apoptotic activity of Bad.Our results showed curcumin might increase the level of Bad by down-regulation of 14-3-3εin HT-29 cells.
To investigate the molecular mechanism of curcumin induced HT-29 cell death and growth inhibiton,we studied the anti-oxidant and pro-oxidant activities of curcumin. The in vitro assay showed curcumin had an effective DPPH~·scavenging,ABTS~+ scavenging,superoxide anion radical scavenging,hydroxyl free radical scavenging, ferric ions(Fe~(3+)) reducing power activities.Curcumin could also inhibit the peroxidation of linoleic acid and the oxidative damage of pBR322 DNA induced by hydroxyl free radical.The in vivo assay showed curcumin could increase the levels of the reactive oxygen species(ROS) and glutathion in HT-29 cells(P＜0.05). N-acetylcysteine(NAC) and catalase pretreatment could significantly inhibit curucmin induced increase of ROS and caspase-3 activation(P＜0.05),which indicated curcumin indcued HT-29 cell apoptosis might be mediated by the stimulated increase of ROS.
引文
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