三氧化二砷抑制腺样囊性癌ACC-2细胞生长、诱导其凋亡的基因表达谱及其分子机制研究
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摘要
目的
本研究拟：(1)研究观察三氧化二砷(arsenic trioxide, As2O3)对腺样囊性癌(adenoid cystic carcinoma, ACC)细胞株ACC-2细胞的生长抑制作用,探讨其诱导ACC-2细胞凋亡的作用机制。(2)检测As2O3药物作用前、后的ACC-2细胞的基因表达谱变化,筛选诱导ACC-2细胞凋亡的相关基因。(3)探讨凋亡相关基因bcl-2、c-myc在As2O3诱导ACC-2细胞凋亡中的作用,验证基因芯片的基因表达谱检测结果,探讨As2O3诱导腺样囊性癌.ACC-2细胞凋亡的分子机制,为临床合理应用As2O3药物提供理论依据。(4)探讨hTERT在As2O3诱导ACC-2细胞凋亡中的作用。(5)探讨线粒体膜电位(Δψm)、Caspase3在As2O3诱导ACC-2细胞凋亡中的作用。
材料与方法
(1)进行ACC-2细胞培养,将As2O3建立不同药物浓度梯度(0、1.0、2.0、4.0、8.0μmol/L)分别作用于ACC-2细胞,在倒置相差显微镜下动态观察培养板中不同浓度As2O3处理前后ACC-2细胞的形态变化,并照相记录;分别在药物作用后24h、48h、72h行MTT染色,酶标仪测得吸光度OD值,计算细胞生长抑制率；行Hoechst33342/PI双染免疫荧光染色,Annexin V-PI双染行流式细胞术分析细胞凋亡率,PI染色行流式细胞术检测DNA含量与细胞周期；用透射电子显微镜观察As2O3作用于ACC-2细胞前后的细胞超微结构变化。(2)应用基因芯片技术检测As2O3药物作用前、后的ACC-2细胞的基因表达谱变化,运用生物信息学分析差异基因的功能网络,获得显著表达差异的候选基因。(3)应用RT-PCR和Western Blot方法,检测As2O3作用前、后,ACC-2细胞的凋亡相关基因bcl-2、c-myc的mRNA水平和蛋白水平的表达。(4)应用RT-PCR方法,检测As2O3作用前、后,ACC-2细胞的hTERT的mRNA水平表达。(5)用Rh123染色,流式细胞仪检测8.0μmol/L As2O3作用前、后(24h),ACC-2细胞的线粒体膜电位(△ψm)变化；用多功能酶标仪进行Caspase3活性检测。
结果
(1)As2O3可抑制腺样囊性癌ACC-2细胞生长,且抑制作用呈现时间-剂量依赖关系；免疫荧光染色观察到随As2O3药物浓度增高,作用时间延长,细胞核被染成强蓝色的凋亡细胞越来越多；透射电子显微镜下的超微结构观察结果,可见ACC-2细胞有部分呈现凋亡的形态,细胞体积缩小,细胞核浓聚缩小,核内出现透明区,核仁消失,核空泡化,染色质固缩,聚集于核膜下,染色质或凝集成团块状部分并附着在核膜下,或染色质边聚,形成新月状,细胞器减少,细胞浆浓缩,或裂解成质膜包绕的染色质碎片(凋亡小体)；流式细胞术结果显示,随As2O3药物作用浓度的增加,ACC-2细胞的凋亡率逐渐增高;除低浓度组(1.0μmol/L)外,其余药物浓度组(2.0、4.0、8.0μmol/L)与对照组相比,其差异有显著性(P<0.05)；药物作用组均可检测到亚G1期凋亡峰,但低浓度组(1.0、2.0μmol/L)的凋亡峰不明显,高浓度组(4.0、8.0μmol/L)的亚G1期凋亡峰明显；4.0、8.0μmol/L的As2O3作用48h后,ACC-2细胞G2-M期细胞数明显增多,与对照组相比,分别上升30.23%和33.43%。(2)As2O3作用于ACC-2细胞后,其基因表达谱发生了较大的变化,有1160个基因显著上调表达；1084个基因显著下调表达。(3)RT-PCR结果显示,在未经药物作用、作为对照组的正常培养的ACC-2细胞中,bcl-2、c-myc的mRNA呈现明显高表达；在As2O3作用于ACC-2细胞后24h与48h时,随As2O3药物浓度的增高(1.0μmol/L、2.0μmol/L、4.0μmol/L、8.0μmol/L),bcl-2、c-myc的mRNA表达逐渐降低。Western Blot结果显示,在未经药物作用、作为对照组的正常培养的ACC-2细胞中,bcl-2、c-myc蛋白呈现明显高表达；在As2O3作用于ACC-2细胞后24h与48h时,随As2O3药物浓度的增高(1.0μmol/L、2.0μmol/L、4.0μmol/L、8.0μmol/L), bcl-2、c-myc蛋白表达逐渐降低,与mRNA表达变化趋势相一致。(4)RT-PCR结果显示,在未经药物作用、作为对照组的正常培养的ACC-2细胞中,hTERT的mRNA呈现明显高表达；在As2O3作用于ACC-2细胞后24h与48h时,随As2O3药物浓度的增高(1.0μmol/L、2.0μmol/L、4.0μmol/L、8.0μimol/L), hTERT的mRNA表达逐渐降低。(5)空白对照组ACC-2细胞内Rh123荧光强度最强,8.0μmol/L As2O3治疗组ACC-2细胞内Rh123荧光强度减弱,其差异有显著性(P<0.05)；随着As2O3药物浓度的增高(0μmol/L,1μmol/L,2μmol/L,4μmol/L,8μmol/L), ACC-2细胞的Caspase3酶活力单位逐渐增加。
结论
(1)As2O3可抑制腺样囊性癌ACC-2细胞生长,主要是通过诱导ACC-2细胞凋亡来实现的；As2O3作用于ACC-2细胞后,细胞呈现出典型的凋亡形态学改变,可以检测到亚G1期凋亡峰,细胞于G2/M期阻滞,细胞凋亡率随As2O3药物浓度的增高而逐渐增高。(2)As2O3作用于ACC-2细胞后,其基因表达谱发生了较大的变化,与凋亡相关的基因变化明显。(3)As2O3通过下调ACC-2细胞的bcl-2、c-myc、hTERT的mRNA转录表达及bcl-2、c-myc的蛋白表达,来诱导ACC-2细胞凋亡。(4)As2O3作用于ACC-2细胞,可通过降低线粒体膜电位从而引起细胞凋亡。随着As2O3药物浓度的增高,ACC-2细胞的Caspase3酶活力单位逐渐增加,Caspase3被激活,细胞随即发生不可逆转的凋亡过程。(5)As2O3诱导腺样囊性癌ACC-2细胞凋亡,至少通过早期下调bcl-2和c-myc的上游mRNA转录表达及下游蛋白表达,同时正相调节hTERT的mRNA转录表达下调,bcl-2蛋白表达抑制,线粒体膜电位下降甚至耗散,从而可造成线粒体外膜通透性增高,MPTP开放,促进Cyt C的释放,激活效应Caspase3,从而发生细胞凋亡,细胞阻滞于G2/M期。As2O3诱导ACC-2细胞凋亡,可能是通过癌基因、抑癌基因、蛋白酶类的多步骤、多因素参与的复杂过程,通过立体交叉网状的信号转导通路来实现的。
Objectives
This study aims to (1)observe the inhibitory effect of arsenic trioxide (As2O3) on adenoid cystic carcinoma (ACC) cell line ACC-2, and to investigate the cellular and molecular mechanisms of As2O3-induced apoptosis in ACC-2cells;(2)detect the changes of gene expression profile of ACC-2cell line before and after AsO3's induction, and to screen the apoptosis-related genes;(3)investigate the role of apoptosis-related genes bcl-2, c-myc in the ACC-2cell apoptosis induced by As2O3, and to verify the gene expression profiling test results of microarray, explore the molecular mechanisms of As2O3-induced apoptosis in human adenoid cystic carcinoma ACC-2cells, provide a theoretical basis for the clinical application of As2O3drugs;(4)explore the role of hTERT in the ACC-2cell apoptosis induced by As2O3;(5)investigate the role of mitochondrial membrane potential (Δψm) and Caspase3in the ACC-2cell apoptosis induced by As2O3.
Methods
(1)ACC-2cells were cultured. The different drug concentration gradient (0,1.0,2.0,4.0,8.0umol/L) of As2O3were applied to ACC-2cells respectively. The morphological changes of ACC-2cells before and after As2O3's induction were observed under inverted phase contrast microscope, and photographic records were taken. MTT assay was performed after As2O3application24h,48h,72h, and the absorbance OD values were measured by TECAN Safire Ⅱ multifunctional microplate reader to get the cell growth inhibition rate. Hoechst33342/PI double staining by immunofluorescence staining was performed. Annexin V-PI double staining was performed by flow cytometry to analyze the apoptosis rate of cells. PI staining was performed by flow cytometry to detect DNA content and cell cycle. The ultrastructural changes of ACC-2cells before and after As2O3's induction were observed by transmission electron microscopy.(2) The gene expression profile of ACC-2cells was detected before and after As2O3's induction with application of gene chip. Bioinformatics analysis was used to explore the functional networks of the differentially expressed genes in order to get the significantly differentially expressed candidate genes.(3) The mRNA levels and protein levels expression of the apoptosis related genes bcl-2, c-myc of ACC-2cells before and after As2O3's induction were detected by RT-PCR and Western Blot.(4) The mRNA expression of hTERT of ACC-2cells before and after As2O3's induction was detected by RT-PCR.(5) The mitochondrial membrane potential (Δψm) of ACC-2cells before and after As2O3's induction (8.0μmol/L for24h) was detected by flow cytometry with Rh123staining. Caspase3activity was detected by the multifunctional microplate reader.
Results
(1) AS2O3could inhibit the adenoid cystic carcinoma ACC-2cells growth, and the inhibition presented a time-dose-dependent relationship. With the increased AS2O3drug concentration and action time, nuclei of apoptosis cells stained strong blue became more and more by immunofluorescence staining. Ultrastructure observation under the transmission electron microscope showed that some of ACC-2cells presenting apoptotic morphology, such as cell shrinkage, nucleus concentrated shrinkage, transparent area in the nucleus, nucleolus disappearing, nuclear vacuolization, chromatin condensation, gathering in the nuclear membrane, or integrating clumps and attaching to the nuclear membrane, or chromatin margination forming of crescent-shaped substances, organelles decreased, cytoplasm concentration, or cracking into the plasma membrane surrounding the chromatin fragments (apoptotoc bodies). Flow cytometry results showed that ACC-2cells apoptosis rate increased gradually with the increase of the concentration of AS2O3. Except for the low concentration group (1.0μmol/L), the others'(2.0,4.0,8.0μmol/L) apoptosis rate were higher, compared with that of the control group, the difference being significant (P<0.05). Sub-G1apoptosis peak was detected in As2O3action groups, among which, sub-G1apoptosis peak was not obvious in the low concentration groups (1.0,2.0umol/L), while it was obvious in the high concentration group (4.0,8.0μmol/L). After4.0.8.0μmol/L As2O3action to ACC-2cells for48h, G2-M phase cells significantly increased. Compared with that of the control group, it was with an increase of30.23%and33.43%, respectively.(2)After As2O3action to ACC-2cells, its gene expression profile changed greatly, with1160genes expression significantly up-regulated, and1084genes significantly downregulated.(3)RT-PCR results showed that bcl-2, c-myc mRNA expression were significantly higher in the control group, while after As2O3action to ACC-2cells for24h and48h, with the increase of As2O3concentration (1.0μmol/L,2.0μmol/L,4.0μmol/L,8.0μmol/L), bcl-2, c-myc mRNA expression decreased gradually. Western Blot results showed that bcl-2, c-myc protein expression were significantly higher in the control group, while after As2O3action to ACC-2cells for24h and48h, with the increase of As2O3concentration (1.0μmol/L,2.0μmol/L,4.0μmol/L,8.0μmol/L), bcl-2, c-myc protein expression decreased gradually. The trend was consistent with mRNA expression.(4)RT-PCR results showed that hTERT mRNA expression was significantly higher in the control group, while after As2O3action to ACC-2cell for24h and48h. with the increase of As2O3concentration (1.0μmol/L,2.0μmol/L,4.0μmol/L,8.0μmol/L), hTERT mRNA expression decreased gradually.(5)Rh123fluorescence intensity in ACC-2cells was the strongest in the control group, while it weakened in ACC-2cells in8.0μmol/L As2O3treatment group. The difference was significant (P<0.05). With the increase of As2O3concentration (0μmol/L,1.0μmol/L,2.0μmol/L,4.Oμmol/L,8.0μmol/L), Caspase3enzyme activity unit in ACC-2cells gradually increased.
Conclusions
(1) As2O3can inhibit the adenoid cystic carcinoma ACC-2cells growth, mainly through the induction of apoptosis. After As2O3treatment to ACC-2cells, the cells show typical morphological changes of apoptosis. Sub-Gi apoptotic peak can be detected and cells are in G2/M phase arrest. The apoptosis rate increased gradually with the increase of As2O3concentration.(2)After As2O3treatment to ACC-2cells, its gene expression profile changed greatly, with the significant changes of apoptosis-related genes.(3) As2O3can induce apoptosis of ACC-2cells by downregulating bcl-2, c-myc, hTERT mRNA transcript expression and bcl-2, c-myc protein expression.(4) As2O3can induce apoptosis of ACC-2cells by reducing the mitochondrial membrane potential. With As2O3concentration increased, Caspase3enzyme activity unit of ACC-2cells gradually increases, which results in activation of the expression of Caspase3, and the cells immediately enter the irreversible apoptosis process.(5)On the whole, As2O3can induce the apoptosis of adenoid cystic carcinoma ACC-2cells, at least through the early downregulating bcl-2, c-myc mRNA transcript expression and protein expression, and positively regulating hTERT mRNA expression downregulation, bcl-2protein expression inhibition, the mitochondrial membrane potential decline or even dissipation, which can cause increased permeability of the mitochondrial outer membrane, MPTP opening up, promoting the release of cytochrome C, activating Caspase3, which occurs in apoptosis, cells arrest at the G2/M phase. As2O3-induced ACC-2cells apoptosis achieves through the complex process in which multi-step, multiple fagtors of oncogenes, tumor suppressor genes, protease are all involved, and through the interchange network of signal transduction pathways.
本研究拟：(1)研究观察三氧化二砷(arsenic trioxide, As2O3)对腺样囊性癌(adenoid cystic carcinoma, ACC)细胞株ACC-2细胞的生长抑制作用,探讨其诱导ACC-2细胞凋亡的作用机制。(2)检测As2O3药物作用前、后的ACC-2细胞的基因表达谱变化,筛选诱导ACC-2细胞凋亡的相关基因。(3)探讨凋亡相关基因bcl-2、c-myc在As2O3诱导ACC-2细胞凋亡中的作用,验证基因芯片的基因表达谱检测结果,探讨As2O3诱导腺样囊性癌.ACC-2细胞凋亡的分子机制,为临床合理应用As2O3药物提供理论依据。(4)探讨hTERT在As2O3诱导ACC-2细胞凋亡中的作用。(5)探讨线粒体膜电位(Δψm)、Caspase3在As2O3诱导ACC-2细胞凋亡中的作用。
材料与方法
(1)进行ACC-2细胞培养,将As2O3建立不同药物浓度梯度(0、1.0、2.0、4.0、8.0μmol/L)分别作用于ACC-2细胞,在倒置相差显微镜下动态观察培养板中不同浓度As2O3处理前后ACC-2细胞的形态变化,并照相记录;分别在药物作用后24h、48h、72h行MTT染色,酶标仪测得吸光度OD值,计算细胞生长抑制率；行Hoechst33342/PI双染免疫荧光染色,Annexin V-PI双染行流式细胞术分析细胞凋亡率,PI染色行流式细胞术检测DNA含量与细胞周期；用透射电子显微镜观察As2O3作用于ACC-2细胞前后的细胞超微结构变化。(2)应用基因芯片技术检测As2O3药物作用前、后的ACC-2细胞的基因表达谱变化,运用生物信息学分析差异基因的功能网络,获得显著表达差异的候选基因。(3)应用RT-PCR和Western Blot方法,检测As2O3作用前、后,ACC-2细胞的凋亡相关基因bcl-2、c-myc的mRNA水平和蛋白水平的表达。(4)应用RT-PCR方法,检测As2O3作用前、后,ACC-2细胞的hTERT的mRNA水平表达。(5)用Rh123染色,流式细胞仪检测8.0μmol/L As2O3作用前、后(24h),ACC-2细胞的线粒体膜电位(△ψm)变化；用多功能酶标仪进行Caspase3活性检测。
结果
(1)As2O3可抑制腺样囊性癌ACC-2细胞生长,且抑制作用呈现时间-剂量依赖关系；免疫荧光染色观察到随As2O3药物浓度增高,作用时间延长,细胞核被染成强蓝色的凋亡细胞越来越多；透射电子显微镜下的超微结构观察结果,可见ACC-2细胞有部分呈现凋亡的形态,细胞体积缩小,细胞核浓聚缩小,核内出现透明区,核仁消失,核空泡化,染色质固缩,聚集于核膜下,染色质或凝集成团块状部分并附着在核膜下,或染色质边聚,形成新月状,细胞器减少,细胞浆浓缩,或裂解成质膜包绕的染色质碎片(凋亡小体)；流式细胞术结果显示,随As2O3药物作用浓度的增加,ACC-2细胞的凋亡率逐渐增高;除低浓度组(1.0μmol/L)外,其余药物浓度组(2.0、4.0、8.0μmol/L)与对照组相比,其差异有显著性(P<0.05)；药物作用组均可检测到亚G1期凋亡峰,但低浓度组(1.0、2.0μmol/L)的凋亡峰不明显,高浓度组(4.0、8.0μmol/L)的亚G1期凋亡峰明显；4.0、8.0μmol/L的As2O3作用48h后,ACC-2细胞G2-M期细胞数明显增多,与对照组相比,分别上升30.23%和33.43%。(2)As2O3作用于ACC-2细胞后,其基因表达谱发生了较大的变化,有1160个基因显著上调表达；1084个基因显著下调表达。(3)RT-PCR结果显示,在未经药物作用、作为对照组的正常培养的ACC-2细胞中,bcl-2、c-myc的mRNA呈现明显高表达；在As2O3作用于ACC-2细胞后24h与48h时,随As2O3药物浓度的增高(1.0μmol/L、2.0μmol/L、4.0μmol/L、8.0μmol/L),bcl-2、c-myc的mRNA表达逐渐降低。Western Blot结果显示,在未经药物作用、作为对照组的正常培养的ACC-2细胞中,bcl-2、c-myc蛋白呈现明显高表达；在As2O3作用于ACC-2细胞后24h与48h时,随As2O3药物浓度的增高(1.0μmol/L、2.0μmol/L、4.0μmol/L、8.0μmol/L), bcl-2、c-myc蛋白表达逐渐降低,与mRNA表达变化趋势相一致。(4)RT-PCR结果显示,在未经药物作用、作为对照组的正常培养的ACC-2细胞中,hTERT的mRNA呈现明显高表达；在As2O3作用于ACC-2细胞后24h与48h时,随As2O3药物浓度的增高(1.0μmol/L、2.0μmol/L、4.0μmol/L、8.0μimol/L), hTERT的mRNA表达逐渐降低。(5)空白对照组ACC-2细胞内Rh123荧光强度最强,8.0μmol/L As2O3治疗组ACC-2细胞内Rh123荧光强度减弱,其差异有显著性(P<0.05)；随着As2O3药物浓度的增高(0μmol/L,1μmol/L,2μmol/L,4μmol/L,8μmol/L), ACC-2细胞的Caspase3酶活力单位逐渐增加。
结论
(1)As2O3可抑制腺样囊性癌ACC-2细胞生长,主要是通过诱导ACC-2细胞凋亡来实现的；As2O3作用于ACC-2细胞后,细胞呈现出典型的凋亡形态学改变,可以检测到亚G1期凋亡峰,细胞于G2/M期阻滞,细胞凋亡率随As2O3药物浓度的增高而逐渐增高。(2)As2O3作用于ACC-2细胞后,其基因表达谱发生了较大的变化,与凋亡相关的基因变化明显。(3)As2O3通过下调ACC-2细胞的bcl-2、c-myc、hTERT的mRNA转录表达及bcl-2、c-myc的蛋白表达,来诱导ACC-2细胞凋亡。(4)As2O3作用于ACC-2细胞,可通过降低线粒体膜电位从而引起细胞凋亡。随着As2O3药物浓度的增高,ACC-2细胞的Caspase3酶活力单位逐渐增加,Caspase3被激活,细胞随即发生不可逆转的凋亡过程。(5)As2O3诱导腺样囊性癌ACC-2细胞凋亡,至少通过早期下调bcl-2和c-myc的上游mRNA转录表达及下游蛋白表达,同时正相调节hTERT的mRNA转录表达下调,bcl-2蛋白表达抑制,线粒体膜电位下降甚至耗散,从而可造成线粒体外膜通透性增高,MPTP开放,促进Cyt C的释放,激活效应Caspase3,从而发生细胞凋亡,细胞阻滞于G2/M期。As2O3诱导ACC-2细胞凋亡,可能是通过癌基因、抑癌基因、蛋白酶类的多步骤、多因素参与的复杂过程,通过立体交叉网状的信号转导通路来实现的。
Objectives
This study aims to (1)observe the inhibitory effect of arsenic trioxide (As2O3) on adenoid cystic carcinoma (ACC) cell line ACC-2, and to investigate the cellular and molecular mechanisms of As2O3-induced apoptosis in ACC-2cells;(2)detect the changes of gene expression profile of ACC-2cell line before and after AsO3's induction, and to screen the apoptosis-related genes;(3)investigate the role of apoptosis-related genes bcl-2, c-myc in the ACC-2cell apoptosis induced by As2O3, and to verify the gene expression profiling test results of microarray, explore the molecular mechanisms of As2O3-induced apoptosis in human adenoid cystic carcinoma ACC-2cells, provide a theoretical basis for the clinical application of As2O3drugs;(4)explore the role of hTERT in the ACC-2cell apoptosis induced by As2O3;(5)investigate the role of mitochondrial membrane potential (Δψm) and Caspase3in the ACC-2cell apoptosis induced by As2O3.
Methods
(1)ACC-2cells were cultured. The different drug concentration gradient (0,1.0,2.0,4.0,8.0umol/L) of As2O3were applied to ACC-2cells respectively. The morphological changes of ACC-2cells before and after As2O3's induction were observed under inverted phase contrast microscope, and photographic records were taken. MTT assay was performed after As2O3application24h,48h,72h, and the absorbance OD values were measured by TECAN Safire Ⅱ multifunctional microplate reader to get the cell growth inhibition rate. Hoechst33342/PI double staining by immunofluorescence staining was performed. Annexin V-PI double staining was performed by flow cytometry to analyze the apoptosis rate of cells. PI staining was performed by flow cytometry to detect DNA content and cell cycle. The ultrastructural changes of ACC-2cells before and after As2O3's induction were observed by transmission electron microscopy.(2) The gene expression profile of ACC-2cells was detected before and after As2O3's induction with application of gene chip. Bioinformatics analysis was used to explore the functional networks of the differentially expressed genes in order to get the significantly differentially expressed candidate genes.(3) The mRNA levels and protein levels expression of the apoptosis related genes bcl-2, c-myc of ACC-2cells before and after As2O3's induction were detected by RT-PCR and Western Blot.(4) The mRNA expression of hTERT of ACC-2cells before and after As2O3's induction was detected by RT-PCR.(5) The mitochondrial membrane potential (Δψm) of ACC-2cells before and after As2O3's induction (8.0μmol/L for24h) was detected by flow cytometry with Rh123staining. Caspase3activity was detected by the multifunctional microplate reader.
Results
(1) AS2O3could inhibit the adenoid cystic carcinoma ACC-2cells growth, and the inhibition presented a time-dose-dependent relationship. With the increased AS2O3drug concentration and action time, nuclei of apoptosis cells stained strong blue became more and more by immunofluorescence staining. Ultrastructure observation under the transmission electron microscope showed that some of ACC-2cells presenting apoptotic morphology, such as cell shrinkage, nucleus concentrated shrinkage, transparent area in the nucleus, nucleolus disappearing, nuclear vacuolization, chromatin condensation, gathering in the nuclear membrane, or integrating clumps and attaching to the nuclear membrane, or chromatin margination forming of crescent-shaped substances, organelles decreased, cytoplasm concentration, or cracking into the plasma membrane surrounding the chromatin fragments (apoptotoc bodies). Flow cytometry results showed that ACC-2cells apoptosis rate increased gradually with the increase of the concentration of AS2O3. Except for the low concentration group (1.0μmol/L), the others'(2.0,4.0,8.0μmol/L) apoptosis rate were higher, compared with that of the control group, the difference being significant (P<0.05). Sub-G1apoptosis peak was detected in As2O3action groups, among which, sub-G1apoptosis peak was not obvious in the low concentration groups (1.0,2.0umol/L), while it was obvious in the high concentration group (4.0,8.0μmol/L). After4.0.8.0μmol/L As2O3action to ACC-2cells for48h, G2-M phase cells significantly increased. Compared with that of the control group, it was with an increase of30.23%and33.43%, respectively.(2)After As2O3action to ACC-2cells, its gene expression profile changed greatly, with1160genes expression significantly up-regulated, and1084genes significantly downregulated.(3)RT-PCR results showed that bcl-2, c-myc mRNA expression were significantly higher in the control group, while after As2O3action to ACC-2cells for24h and48h, with the increase of As2O3concentration (1.0μmol/L,2.0μmol/L,4.0μmol/L,8.0μmol/L), bcl-2, c-myc mRNA expression decreased gradually. Western Blot results showed that bcl-2, c-myc protein expression were significantly higher in the control group, while after As2O3action to ACC-2cells for24h and48h, with the increase of As2O3concentration (1.0μmol/L,2.0μmol/L,4.0μmol/L,8.0μmol/L), bcl-2, c-myc protein expression decreased gradually. The trend was consistent with mRNA expression.(4)RT-PCR results showed that hTERT mRNA expression was significantly higher in the control group, while after As2O3action to ACC-2cell for24h and48h. with the increase of As2O3concentration (1.0μmol/L,2.0μmol/L,4.0μmol/L,8.0μmol/L), hTERT mRNA expression decreased gradually.(5)Rh123fluorescence intensity in ACC-2cells was the strongest in the control group, while it weakened in ACC-2cells in8.0μmol/L As2O3treatment group. The difference was significant (P<0.05). With the increase of As2O3concentration (0μmol/L,1.0μmol/L,2.0μmol/L,4.Oμmol/L,8.0μmol/L), Caspase3enzyme activity unit in ACC-2cells gradually increased.
Conclusions
(1) As2O3can inhibit the adenoid cystic carcinoma ACC-2cells growth, mainly through the induction of apoptosis. After As2O3treatment to ACC-2cells, the cells show typical morphological changes of apoptosis. Sub-Gi apoptotic peak can be detected and cells are in G2/M phase arrest. The apoptosis rate increased gradually with the increase of As2O3concentration.(2)After As2O3treatment to ACC-2cells, its gene expression profile changed greatly, with the significant changes of apoptosis-related genes.(3) As2O3can induce apoptosis of ACC-2cells by downregulating bcl-2, c-myc, hTERT mRNA transcript expression and bcl-2, c-myc protein expression.(4) As2O3can induce apoptosis of ACC-2cells by reducing the mitochondrial membrane potential. With As2O3concentration increased, Caspase3enzyme activity unit of ACC-2cells gradually increases, which results in activation of the expression of Caspase3, and the cells immediately enter the irreversible apoptosis process.(5)On the whole, As2O3can induce the apoptosis of adenoid cystic carcinoma ACC-2cells, at least through the early downregulating bcl-2, c-myc mRNA transcript expression and protein expression, and positively regulating hTERT mRNA expression downregulation, bcl-2protein expression inhibition, the mitochondrial membrane potential decline or even dissipation, which can cause increased permeability of the mitochondrial outer membrane, MPTP opening up, promoting the release of cytochrome C, activating Caspase3, which occurs in apoptosis, cells arrest at the G2/M phase. As2O3-induced ACC-2cells apoptosis achieves through the complex process in which multi-step, multiple fagtors of oncogenes, tumor suppressor genes, protease are all involved, and through the interchange network of signal transduction pathways.
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