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硝普钠诱导K562细胞凋亡过程STAT3/P38MAPK活化

期刊目录网精神医学论文发表2013-12-25 16:20关注(1)

  【摘要】STAT3是信号转导和转录活化因子(signal transducers and activators of transcription,Stats)家族中的重要成员,接受生长因子、细胞因子的刺激,调节细胞的生长、分化、恶性转化和凋亡[2,3]。端粒酶对于细胞的永生化、凋亡、恶性转化和衰老等起着重要作用,在绝大多数肿瘤细胞中端粒酶活性表达显著增加。

  【关键词】 硝普钠,一氧化氮,K562细胞,细胞凋亡,STAT3,P38MAPK,端粒酶,hTERT-mRNA

  Effects of Sodium Nitroprusside on P38MAPK/STAT3 Activation

  and Telomerase Reverse Transcriptase mRNA Expression in

  Inducing Apoptosis of K562 Cell Line

  Abstract This study was aimed to investigate the activation of P38MAPK/STAT3 and expression of telomerase reverse transcriptase during sodium nitroprusside (SNP) inducing apoptosis of human leukemia cell line K562 and to explore the molecular mechanisms of SNP-inducing apoptosis in K562 cells. The K562 cell were treated with different concentrations of SNP and were cultured for different time. Cell apoptosis was analysed by cell morphology,DNA agarose gel electrophoresis, DNA content,and Annexin-V/PI labeling method. The TdT-mediated dUTP nick end labeling (TUNEL) assay was used to quantitate the in situ cell apoptosis. The expressions of phosphorylated p38MAPK or STAT3 were analysed by flow cytometry,while the expression of hTERT mRNA in transcriptional level was measured by fluorescence quantitative RT-PCR. The results showed that SNP inhibited K562 cell growth. The K562 cell apoposis was comfirmed by typical cell morphology and DNA fragment,peak of sub-G1 phase,TUNEL and Annexin-Ⅴ/PI labeling. A majority of K562 cells were arrested in G0/G1 phase. After treatment with SNP at 0.5-3.0 mmol/L,the expression of phosphorylated-P38MAPK and phosphorylated-STAT3 increased first and decreased afterwards. Incubation of K562 cell with SNP (2 mmol/L) could increase the expression of phosphorylated-P38MAPK and phosphorylated-STAT3 at 12 hours and 24 hours respectively,and down-regulated at 72 hours and 48 hours. SNP could decrease the expression of hTERT-mRNA in time-and dose-dependent manner. It is concluded that SNP can significantly induce K562 cells apoptosis,its mechanism may be related to the activation of P38MAPK and suppression of phospho

  rylated-STAT3 and hTRET-mRNA.

  Key words sodium nitroprusside; nitric oxide; K562 cell; apoptosis; STAT3; P38MAPK; telomerase; hTERT mRNA

为了研究外源性一氧化氮供体硝普钠(SNP)诱导K562细胞凋亡过程中STAT3及P38MAPK活化及端粒酶hTERT-mRNA表达的变化,探讨硝普钠诱导K562细胞凋亡机制,用Annexin-V/PI双标记、DNA片段原位末端标记法、DNA凝胶电泳、DNA含量及细胞周期分析等方法检测细胞凋亡。用流式细胞术测定经硝普钠干预后K562细胞磷酸化P38MAPK和磷酸化STAT3的表达,同时利用实时荧光PCR定量检测端粒酶hTERT-mRNA表达的变化。

  结果表明: K562细胞经硝普钠作用后出现典型的细胞形态改变,DNA片段化,显现亚G1峰Ⅱ并显著增加。Annexin-V/PI和DNA片段原位末端标记表达增加。这些均证实NO能诱导K562细胞凋亡,大部分细胞阻滞于G0/G1期。

  SNP诱导K562细胞凋亡过程中,磷酸化P38MAPK和磷酸化STAT3的表达随SNP浓度的增加而表现为先增强后下降;K562细胞与2.0 mmol/L SNP孵育不同的时间内,磷酸化P38MAPK的表达在12小时时达到高峰并持续至48小时,72小时后表达下降;磷酸化STAT3的表达在24小时时达高峰,48小时后表达即显著下降;端粒酶hTERT-mRNA的表达随SNP作用的浓度增加和时间延长而显著下调。结论:SNP能诱导K562细胞凋亡,其机制可能与P38MAPK的活化、抑制端粒酶逆转录酶和STAT3的活化有关。

  有丝分裂原激活蛋白激酶(mitogen-activated protein kinase,MAPK) 信号通路参与了细胞生长、发育、分裂及细胞间的功能同步等生理过程和细胞恶性转化等病理过程。P38MAPK是MAPK家族的重要成员,可被多种因子和环境应激反应激活,介导细胞增殖、分化和凋亡[1]。

  以端粒酶作为治疗靶点,抑制端粒酶活性可为临床治疗肿瘤提供一种新的策略[4]。生物体内的NO是一种反应极强的效应分子,也是体内发现的第一个气体信使分子。我们的前期研究已证实,用硝普钠(sodium nitroprusside,SNP)作为外源性的NO供体,可通过细胞阻滞于G0/G1期而显著抑制K562细胞的增殖并诱导K562细胞凋亡。

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