Adenoviral-mediated interferon a overcomes resistance to the interferon protein in various cancer types and has marked bystander effects
Adenoviral-mediated interferon a overcomes resistance to the interferon protein in various cancer types and has marked bystander effects
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DOI：
10.1038/sj.cgt.7701011
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发表时间：
2007-03-01
影响因子：
6.4
通讯作者：
Benedict, W. F.
中科院分区：
文献类型：
--
作者：
Zhang, X.;Yang, Z.;Benedict, W. F.
我们先前已经证明，膀胱内注射编码人干扰素α-2b的腺病毒(Ad-干扰素)可诱导体外对超过100万单位/毫升干扰素α蛋白耐药的细胞所产生的浅表性人膀胱癌显著消退。此外，Ad-干扰素似乎产生了很强的旁观者效应。在这项研究中，我们发现，在不同类型的肿瘤细胞中，Ad-干扰素对细胞生长和凋亡有明显的抑制作用，所有这些细胞对干扰素α蛋白都具有耐药性。此外，在所有的细胞株中，在腺病毒-干扰素基因转染组中均可见较强的核周干扰素染色，而在干扰素蛋白作用下则未见此染色。Ad-干扰素诱导caspase3、8和9的蛋白水解性加工，表明caspase3、8和9被激活。然而，Caspase-8选择性抑制剂IETDfmk仅阻断对干扰素α蛋白敏感的细胞株的凋亡，而对Ad-干扰素诱导的caspase-3或-9处理和细胞死亡的影响很小，表明死亡受体非依赖机制(S)参与了对干扰素α蛋白耐药的癌细胞的细胞毒作用。此外，我们还证明了一种尚未确定的可溶性因子(S)是导致在干扰素蛋白耐药癌细胞中观察到的Ad干扰素治疗后的旁观者效应的原因。
We have previously shown that intravesical administration of adenovirus encoding human interferon alpha-2b (Ad-IFN) induced a marked regression of superficial human bladder tumors derived from cells that are resistant to over 1 million units/ml of IFN alpha protein in vitro. In addition, Ad-IFN appeared to produce strong bystander effects. In this study, we show that Ad-IFN causes marked inhibition of cell growth and apoptosis in cells of various tumor types, all of which are resistant to IFN alpha protein. In addition, strong perinuclear IFN staining was seen in all cell lines following Ad-IFN transfection and was never observed after exposure to the IFN protein. Ad-IFN induced proteolytic processing of caspases 3, 8 and 9, indicative of enzymatic activation. However, the caspase-8-selective inhibitor, IETDfmk, blocked apoptosis only in the cell lines that were sensitive to the IFN alpha protein and had minimal effect on Ad-IFN-induced caspase-3 or -9 processing and cell death, indicating that death receptor-independent mechanism(s) were involved in the cytotoxic effects observed for cancer cell lines resistant to the IFN alpha protein. Moreover, we document that a yet to be identified soluble factor(s) is responsible for causing the bystander effect observed following Ad-IFN treatment in IFN protein-resistant cancer cells.