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首页> 外文期刊>Oncogene >Mechanism of cytosine arabinoside-mediated apoptosis: role of Rel A (p65) dephosphorylation
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Mechanism of cytosine arabinoside-mediated apoptosis: role of Rel A (p65) dephosphorylation

机译：胞嘧啶阿拉伯糖苷介导的细胞凋亡的机制：Rel A（p65）去磷酸化的作用

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Nuclear transcription factor kappa B (NF-B) has been shown both to block apoptosis and to promote cell proliferation, and hence has been considered an important target for anticancer drug development. The pyrimidine analogue cytosine arabinoside (araC) is among the most effective agents used in the treatment of acute leukemia, and we demonstrate in this study that its chemotherapeutic activity may be mediated by its inhibition of NF-B. We found that in Jurkat cells, although tumor necrosis factor (TNF), araC, or ceramide induced NF-B, the induction was only transient in the case of araC. In both HuT-78 and serum-activated LPS-stimulated Jurkat (SA-LPS/Jkt) cells that expressed NF-B, TNF or ceramide treatments did not affect the NF-B expression whereas araC downregulated it. AraC, but not TNF or ceramide was able to induce apoptosis in these cells as detected by assays for lipid peroxidation, reactive oxygen intermediates generation, caspase activation, cytotoxicity, Bcl-2 degradation, and DNA fragmentation. AraC also potentiated apoptosis mediated by cis-platin, etoposide, or taxol in these cells. AraC was able to induce protein phosphatases (PP) 2A and 2B-A, and phosphorylation of p65 subunit of NF-B in the HuT-78 and SA-LPS/Jkt cells was downregulated by araC treatment. Furthermore, calyculin A, a specific phospho-serine/phospho-threonine phosphatase inhibitor, protected HuT-78 and SA-LPS/Jkt cells from araC-mediated NF-B downregulation and apoptosis. These observations collectively suggest that araC induces apoptosis in NF-B-expressing cells by dephosphorylating the p65 subunit of NF-B.
机译：核转录因子κB（NF-B）已被证明既可以阻止细胞凋亡，又可以促进细胞增殖，因此被认为是抗癌药物开发的重要目标。嘧啶类似物胞嘧啶阿拉伯糖苷（araC）是用于治疗急性白血病的最有效药物，我们在这项研究中证明了其化学治疗活性可能是由其对NF-B的抑制作用介导的。我们发现在Jurkat细胞中，尽管肿瘤坏死因子（TNF），araC或神经酰胺诱导了NF-B，但诱导仅在araC情况下是短暂的。在表达NF-B的HuT-78和血清激活的LPS刺激的Jurkat（SA-LPS / Jkt）细胞中，TNF或神经酰胺处理均不影响NF-B的表达，而araC下调它。通过脂质过氧化，活性氧中间体生成，胱天蛋白酶激活，细胞毒性，Bcl-2降解和DNA片段化的检测，AraC能够诱导这些细胞的凋亡，但TNF或神经酰胺却不能。 AraC还可以增强顺铂，依托泊苷或紫杉醇介导的细胞凋亡。 AraC能够诱导蛋白磷酸酶（PP）2A和2B-A，并且通过araC处理下调了HuT-78和SA-LPS / Jkt细胞中NF-B的p65亚基的磷酸化。此外，特定的磷酸丝氨酸/磷酸苏氨酸磷酸酶抑制剂calyculin A保护HuT-78和SA-LPS / Jkt细胞免受araC介导的NF-B下调和凋亡。这些观察结果共同表明araC通过使NF-B的p65亚基去磷酸化而诱导表达NF-B的细胞凋亡。

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