Nitric oxide regulates cell sensitivity to cisplatin-induced apoptosis through S-nitrosylation and inhibition of Bcl-2 ubiquitination
Nitric oxide regulates cell sensitivity to cisplatin-induced apoptosis through S-nitrosylation and inhibition of Bcl-2 ubiquitination
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DOI：
10.1158/0008-5472.can-05-4533
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发表时间：
2006-06-15
期刊：
影响因子：
11.2
通讯作者：
Rojanasakul, Yon
中科院分区：
文献类型：
--
作者：
Chanvorachote, Pithi;Nimmannit, Ubonthip;Rojanasakul, Yon
顺铂是一种有效的细胞毒性药物，常用于治疗实体瘤。然而，肿瘤细胞对顺铂诱导的细胞凋亡的获得性抗性是有效治疗的主要限制，如在人肺癌中经常观察到的。一氧化氮（NO）是细胞凋亡的关键调节因子，但其在顺铂诱导的细胞死亡中的作用及其机制尚不清楚。以往的研究表明，肺癌中NO合酶活性增加和NO产生增加，这与化疗耐药的发生率相关。在这里，我们表明，NO损害细胞的凋亡功能，并增加其抵抗顺铂诱导的细胞死亡在人肺癌H-460细胞。NO供体硝普钠和二亚丙基三胺NONOate能抑制顺铂诱导的细胞死亡，而NO抑制剂氨基胍和2-（4-羧基苯基）-4，4，5，5-四甲基咪唑啉-1-氧基-3-氧化物则相反。H-460细胞对顺铂的耐药是由Bcl-2介导的，NO通过泛素-蛋白酶体途径抑制Bcl-2的降解，上调Bcl-2的表达。顺铂诱导的活性氧的产生导致Bcl-2的去磷酸化和降解。相反，一代。NO对Bcl-2磷酸化没有影响，但诱导蛋白质的S-亚硝基化，从而抑制其遍在化和随后的蛋白酶体降解。这些研究结果表明，一种新的途径，NO调节Bcl-2，这提供了一个关键的机制，顺铂耐药及其潜在的调制改善癌症化疗。
Cisplatin is a potent cytotoxic agent commonly used for the treatment of solid tumors. However, tumor cell-acquired resistance to cisplatin-induced apoptosis is a major limitation for efficient therapy, as frequently observed in human lung cancer. Nitric oxide (NO) is a key regulator of apoptosis, but its role in cisplatin-induced cell death and the underlying mechanism are largely unknown. Previous studies indicate increased NO synthase activity and elevated NO production in lung carcinomas, which correlate with the incidence of chemotherapeutic resistance. Here, we show that NO impairs the apoptotic function of cells and increases their resistance to cisplatin-induced cell death in human lung carcinoma H-460 cells. The NO donors sodium nitroprusside and dipropylenetriamine NONOate were able to inhibit cisplatin-induced cell death, whereas the NO inhibitors aminoguanidine and 2-(4-carboxyphenyl)-4,4,5,5-tetra-methylimidazoline-1-oxyl-3-oxide had opposite effect. Cisplatin resistance in H-460 cells is mediated by Bcl-2, and NO up-regulates its expression by preventing the degradation of Bcl-2 via ubiquitin-proteasome pathway. Cisplatin-induced generation of reactive oxygen species causes dephosphorylation and degradation of Bcl-2. In contrast, generation of. NO has no effect on Bcl-2 phosphorylation but induces S-nitrosylation of the protein, which inhibits its ubiquitination and subsequent proteasomal degradation. These findings indicate a novel pathway for NO regulation of Bcl-2, which provides a key mechanism for cisplatin resistance and its potential modulation for improved cancer chemotherapy.