Nitric oxide and ionizing radiation synergistically promote apoptosis and growth inhibition of cancer by activating p53
Nitric oxide and ionizing radiation synergistically promote apoptosis and growth inhibition of cancer by activating p53
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DOI：
10.1158/0008-5472.can-04-2212
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发表时间：
2004-11-01
期刊：
影响因子：
11.2
通讯作者：
Blumberg, D
中科院分区：
文献类型：
--
作者：
Cook, T;Wang, Z;Blumberg, D
一氧化氮 (NO) 是一种有效的肿瘤放射增敏剂；然而，其临床应用受到全身副作用的限制。我们之前已经证明，将人类诱导型一氧化氮合酶（iNOS）基因转移到肿瘤细胞和肿瘤中会诱导高输出一氧化氮的产生，从而显着增强肿瘤的放射反应性，并且没有观察到副作用。值得注意的是，iNOS 基因转移通过凋亡细胞死亡增强肿瘤放射反应性。由于已知 NO 和电离辐射都会促进 p53 依赖性细胞凋亡，因此我们假设 p53 激活可能是这两种基因毒性应激协同作用的主要机制。我们报道，NO和电离辐射通过增强p53丝氨酸15的磷酸化，协同激活无胸腺小鼠结直肠癌中的p53。在p53敲除的同基因癌细胞系中，NO和电离辐射对肿瘤细胞凋亡和肿瘤放射反应性的影响显着降低。此外，将p53和iNOS基因同时转移到缺乏功能性p53的肿瘤细胞中比单独转移任一基因更能增强它们的放射反应性。
Nitric oxide (NO) is a potent tumor radiosensitizer; however, its clinical use is limited by systemic side effects. We have demonstrated previously that gene transfer of the human inducible NO synthase (iNOS) gene into tumor cells and tumors induces high-output NO production that significantly enhances tumor radioresponsiveness, with no observed side effects. Notably, iNOS gene transfer enhances tumor radioresponsiveness via apoptotic cell death. Because NO and ionizing radiation are both known to promote p53-dependent apoptosis, we hypothesized that p53 activation might be a primary mechanism for the synergy of these two genotoxic stresses. We report that NO and ionizing radiation synergistically activate p53 in colorectal cancers grown in athymic mice by augmenting phosphorylation of p53 at serine 15. The effect of NO and ionizing radiation on tumor cell apoptosis and tumor radioresponsiveness is significantly reduced in p53 knockout isogenic cancer cell lines. Furthermore, the transfer of both p53 and iNOS genes into tumor cells lacking functional p53 enhanced their radioresponsiveness more than transfer of either gene alone.