Nitric oxide mediates apoptosis induction selectively in transformed fibroblasts compared to nontransformed fibroblasts
Nitric oxide mediates apoptosis induction selectively in transformed fibroblasts compared to nontransformed fibroblasts
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DOI：
10.1093/carcin/23.6.929
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发表时间：
2002-06-01
期刊：
影响因子：
4.7
通讯作者：
Bauer, G
中科院分区：
文献类型：
--
作者：
Heigold, S;Sers, C;Bauer, G
一氧化氮 (NO) 介导具有组成型 src 或诱导 ras 癌基因表达的成纤维细胞的凋亡诱导，而未转化的亲本细胞和回复体不受影响。转化表型与 NO 介导的细胞凋亡诱导敏感性之间的这种直接联系似乎是基于最近描述的转化细胞产生细胞外超氧阴离子，因为转化细胞中 NO 介导的细胞凋亡诱导受到细胞外超氧化物歧化酶 (SOD)、SOD 模拟物和夹竹桃麻素 (NADPH 氧化酶抑制剂) 的抑制。此外，当补充黄嘌呤氧化酶/黄嘌呤作为超氧阴离子的细胞外来源时，无反应的非转化细胞可以对NO介导的细胞凋亡诱导敏感。由于超氧阴离子和 NO 很容易在扩散控制反应中相互作用生成过氧亚硝酸盐，因此过氧亚硝酸盐似乎是 NO 介导的细胞凋亡诱导中负责的细胞凋亡诱导剂。与这一结论一致，过氧亚硝酸盐清除剂依布硒啉和 FeTPPS 抑制了产生超氧阴离子的转化细胞中 NO 介导的细胞凋亡诱导。此外，直接应用过氧亚硝酸盐在转化细胞和非转化细胞中均诱导细胞凋亡，这表明过氧亚硝酸盐本身不是选择性凋亡诱导剂，但NO在转化细胞中选择性诱导细胞凋亡是通过选择性过氧亚硝酸盐生成来实现的。 NO 与靶细胞衍生的超氧阴离子的相互作用代表了转化细胞中选择性凋亡诱导的新概念。这种机制可能是利用 NO 发挥抗肿瘤作用的天然抗肿瘤系统（如巨噬细胞、自然杀伤细胞、粒细胞）选择性诱导细胞凋亡的基础。 NO 介导的细胞凋亡诱导涉及线粒体去极化，并被 Bcl-2 过表达所阻断。
Nitric oxide (NO) mediates apoptosis induction in fibroblasts with constitutive src or induced ras oncogene expression, whereas nontransformed parental cells and revertants are not affected. This direct link between the transformed phenotype and sensitivity to NO-mediated apoptosis induction seems to be based on the recently described extracellular superoxide anion generation by transformed cells, as NO-mediated apoptosis induction in transformed cells is inhibited by extracellular superoxide dismutase (SOD), by SOD mimetics and by apocynin, an inhibitor of NADPH oxidase. Furthermore, nonresponsive nontransformed cells can be rendered sensitive for NO-mediated apoptosis induction when they are supplemented with xanthine oxidase/xanthine as an extracellular source for superoxide anions. As superoxide anions and NO readily interact in a diffusion-controlled reaction to generate peroxynitrite, peroxynitrite seems to be the responsible apoptosis inducer in NO-mediated apoptosis induction. In line with this conclusion, NO-mediated apoptosis induction in superoxide anion-generating transformed cells is inhibited by the peroxynitrite scavengers ebselen and FeTPPS. Moreover, direct application of peroxynitrite induces apoptosis both in transformed and nontransformed cells, indicating that peroxynitrite is no selective apoptosis inducer per se, but that selective apoptosis induction in transformed cells by NO is achieved through selective peroxynitrite generation. The interaction of NO with target cell derived superoxide anions represents a novel concept for selective apoptosis induction in transformed cells. This mechanism may be the basis for selective apoptosis induction by natural antitumor systems (like macrophages, natural killer cells, granulocytes) that utilize NO for antitumor action. Apoptosis induction mediated by NO involves mitochondrial depolarization and is blocked by Bcl-2 overexpression.