Direct cytotoxicity produced by adenoviral-mediated interferon α gene transfer in interferon-resistant cancer cells involves ER stress and caspase 4 activation.
Direct cytotoxicity produced by adenoviral-mediated interferon α gene transfer in interferon-resistant cancer cells involves ER stress and caspase 4 activation.
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DOI：
10.1038/cgt.2011.26
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发表时间：
2011-09
影响因子：
6.4
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中科院分区：
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在过去的几年里，我们已经获得了大量的证据表明，Ad-IFNα可以克服对IFNα蛋白本身的耐药性。由于感染了Ad-IFNα的癌细胞也显示出高的核周细胞质IFNα表达，我们对内质网（ER）应激和caspase 4的裂解是否在Ad-IFNα导致癌细胞死亡中起主要作用感兴趣。事实上，在Ad-IFNα与IFNα染色和ER跟踪器共定位的癌细胞感染后12小时，procaspase 4就上调并分裂。相比之下，永生化的正常人尿路上皮细胞，虽然表现出类似的核周IFNα染色，但没有发现裂解的caspase 4。Caspase 4的裂解未被Caspase 8特异性抑制剂z-IETD阻断，表明Caspase 4的激活独立于Caspase 8的激活。阻断caspase 4也能抑制Ad-IFNα细胞中caspase 3的激活。最后，在膀胱内接受Ad-IFNα/Syn3治疗的患者尿液中，在Ad-IFNα阳性癌细胞中检测到裂解形式的caspase 4 （p10）。因此，内质网应激和caspase 4的激活似乎是Ad-IFNα直接导致癌细胞死亡的重要机制，也发生在临床环境中。
Over the past several years we have obtained considerable evidence indicating that Ad-IFNα can overcome resistance to the IFNα protein itself. Since cancer cells infected with Ad-IFNα also show high perinuclear cytoplasmic IFNα expression we were interested in whether endoplasmic reticulum (ER) stress and cleavage of caspase 4 could play a major role Ad-IFNα produced cancer cell death. Indeed procaspase 4 was upregulated and cleaved as early as 12 hours after Ad-IFNα infection of the cancer cells which co-localized with IFNα staining and ER tracker. In contrast immortalized normal human urothelial cells, although exhibiting similar perinuclear IFNα staining showed no cleaved caspase 4. Caspase 4 cleavage was not blocked by the caspase 8 specific inhibitor z-IETD, indicating that caspase 4 activation was independent of caspase 8 activation. Blocking caspase 4 also inhibited activation of caspase 3 in Ad-IFNα containing cells. Finally, the cleaved form of caspase 4 (p10) was detected in Ad-IFNα positive cancer cells from the urine of a patient following intravesical Ad-IFNα/Syn3 treatment. Therefore ER stress and activation of caspase 4 appears to be an important mechanism involved in the direct cancer cell death produced by Ad-IFNα and also occurs in the clinical setting.