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首页> 外文学位 >Inhibition of heat-induced apoptosis in human tumor cells by heat shock protein 70 occurs upstream of mitochondrial membrane permeabilization through suppression ofc-Jun N-terminal kinase activity.
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Inhibition of heat-induced apoptosis in human tumor cells by heat shock protein 70 occurs upstream of mitochondrial membrane permeabilization through suppression ofc-Jun N-terminal kinase activity.

机译：通过抑制c-Jun N端激酶活性，热激蛋白70抑制人肿瘤细胞中的热诱导细胞凋亡发生在线粒体膜通透性的上游。

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摘要

Exposure of cells to hyperthermia induces the synthesis of heat shock proteins. These molecular chaperones help cells cope with protein-damaging stresses by preventing and repairing misfoided proteins. Overexpression of heat shock protein 70 (Hsp70) can protect cells from stress-induced apoptosis. Several studies have revealed multiple mechanisms of apoptosis suppression by Hsp70, including effects occurring both upstream and downstream of mitochondrial membrane permeabilization. Hsp70 is often overexpressed in tumor cells and inhibition of stress-induced apoptosis by Hsp70 is believed to be a contributing factor in tumorigenesis. Suppression of this ability could increase the effectiveness of anti-tumor therapy. Tumor cells exist in an acidic environment, although their intracellular pH is maintained in a physiological range. Acute acidification can sensitize tumor cells to heat-induced cell death. However, the ability of Hsp70 to prevent apoptosis under these conditions has not been examined. The objectives of this thesis were to examine the role of Hsp70 in suppressing heat-induced apoptosis and to evaluate the ability of Hsp70 to suppress apoptosis under conditions of acute acidification. A human acute lymphoblastic T cell line with tetracycline-regulated expression of Hsp70 was used for these studies. Hsp70 was found to inhibit stress-induced c-jun N-terminal kinase (JNK) activation and this inhibition prevented apoptosis by blocking the translocation of the pro-apoptotic protein Bax (B cell lymphoma 2 associated protein X) to mitochondria. Inhibition of JNK with SP600125 or by expression of a dominant negative mutant of JNK blocked Bax translocation as effectively as Hsp70 overexpression. Furthermore, acute acidification sensitized Hsp70-expressing cells to heat-induced apoptosis and this was correlated with a reduced ability to suppress JNK activation. These results indicate that Hsp70 blocks heat-induced apoptosis by inhibiting JNK mediated Bax translocation. As well, the ability of Hsp70 to suppress JNK is compromised when cells are exposed to hyperthermia in an acidic environment resulting in elevated levels of apoptosis. This suggests that the tumor cell environment may be exploited to increase the effectiveness of thermal therapy of tumor cells with elevated levels of Hsp70.
机译：细胞暴露于高温会诱导热激蛋白的合成。这些分子伴侣通过防止和修复错误识别的蛋白质，帮助细胞应对蛋白质破坏性压力。热休克蛋白70（Hsp70）的过度表达可以保护细胞免受应激诱导的细胞凋亡。几项研究揭示了Hsp70抑制细胞凋亡的多种机制，包括在线粒体膜通透性上游和下游均发生的作用。 Hsp70通常在肿瘤细胞中过表达，并且据信Hsp70抑制应激诱导的细胞凋亡是肿瘤发生的一个重要因素。抑制这种能力可以提高抗肿瘤治疗的有效性。肿瘤细胞存在于酸性环境中，尽管它们的细胞内pH值保持在生理范围内。急性酸化可使肿瘤细胞对热诱导的细胞死亡敏感。但是，尚未检查Hsp70在这些条件下防止细胞凋亡的能力。本文的目的是研究Hsp70在抑制热诱导的细胞凋亡中的作用，并评估Hsp70在急性酸化条件下抑制细胞凋亡的能力。具有四环素调节的Hsp70表达的人急性淋巴细胞T细胞系用于这些研究。发现Hsp70抑制应激诱导的c-jun N末端激酶（JNK）活化，并且该抑制作用通过阻止促凋亡蛋白Bax（B细胞淋巴瘤2相关蛋白X）向线粒体的转运而阻止了凋亡。用SP600125抑制JNK或通过JNK显性负突变体的表达抑制Bax易位与Hsp70过表达一样有效。此外，急性酸化使表达Hsp70的细胞对热诱导的细胞凋亡敏感，这与抑制JNK激活的能力降低有关。这些结果表明，Hsp70通过抑制JNK介导的Bax移位来阻断热诱导的细胞凋亡。同样，当细胞在酸性环境中暴露于高温时，Hsp70抑制JNK的能力也会受损，导致凋亡水平升高。这表明可以利用肿瘤细胞环境来提高具有升高水平的Hsp70的肿瘤细胞的热疗法的有效性。

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  • 作者

    Lachapelle, Guillaume.;

  • 作者单位

    University of Guelph (Canada).;

  • 授予单位 University of Guelph (Canada).;
  • 学科 Biology Molecular.
  • 学位 Ph.D.
  • 年度 2008
  • 页码 184 p.
  • 总页数 184
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 分子遗传学;
  • 关键词

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