NO signaling confers cytoprotectivity through the survivin network in ovarian carcinomas
NO signaling confers cytoprotectivity through the survivin network in ovarian carcinomas
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DOI：
10.1158/0008-5472.can-08-0406
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发表时间：
2008-07-01
期刊：
影响因子：
11.2
通讯作者：
Stauber, Roland H.
中科院分区：
文献类型：
--
作者：
Engels, Knut;Knauer, Shirley K.;Stauber, Roland H.
尽管在上皮性卵巢癌（EOC）的治疗中取得了相当大的成功，但治疗耐药性抵消了长期生存的改善。生存素作为细胞凋亡抑制剂和有丝分裂调节剂的双重作用与疾病结局相关。然而，生存素在EOC中表达失调的分子机制还需要进一步研究。在这里，我们发现，大量的一氧化氮（NO）供体，S-亚硝基-N-乙酰青霉胺（SNAP）和硝普钠（SNP）或诱导型一氧化氮合酶（iNOS）的过表达通过p38 MAPK途径抑制生存素水平，并引发卵巢癌细胞系（OCC）的凋亡。重要的是，低NO浓度赋予对卡铂/紫杉醇诱导的细胞凋亡的抗性。细胞保护作用是由生存素介导的，因为我们观察到其上调后，低SNAP/SNP剂量或异位表达的少量iNOS。此外，RNAi介导的生存素耗竭阻断了NO信号传导的抗凋亡作用。生存素的诱导涉及磷脂酰肌醇-3-激酶（PI 3 K）/Akt途径的激活，其被PI 3 K抑制剂LY 294002拮抗。有趣的是，iNOS抑制剂1400 W与RNAi介导的生存素下调一起应用协同增强了OCC中药物诱导的凋亡。iNOS/Survivin的相互依赖性似乎也具有临床意义，因为免疫组化显示，在卡铂/紫杉醇治疗的术后残留肿瘤最少的EOC患者（n = 54）中，低iNOS水平与Survivin表达相关（P < 0.01）。此外，iNOS和生存素表达与疾病进展风险增加相关。我们的研究揭示了一种新的分子机制，即NO信号如何通过调节生存素表达而导致卵巢癌的治疗抵抗。因此，药物遗传学iNOS/生存素靶向策略可用于补充EOC的当前治疗方式。
Despite considerable success in the treatment of epithelial ovarian cancer (EOC), therapy resistance counteracts improvement of long-term survival. The dual role of survivin as an apoptosis inhibitor and mitotic regulator has been associated with disease outcome. However, the molecular mechanisms involved in the deregulated expression in EOC of survivin need further investigation. Here, we show that high amounts of the nitric oxide (NO) donors, S-nitroso-N-acetyl-penicillamine (SNAP) and sodium nitroprusside (SNP) or strong overexpression of the inducible nitric oxide synthase (iNOS) suppressed survivin levels via the p38MAPK pathway and triggered apoptosis in ovarian cancer cell lines (OCC). Importantly, low NO concentrations conferred resistance against carboplatin/paclitaxel-induced apoptosis. Cytoprotection was mediated by survivin because we observed its up-regulation subsequent to low SNAP/SNP doses or ectopic expression of low amounts of iNOS. Also, RNAi-mediated depletion of survivin blocked the antiapoptotic effects of NO signaling. Induction of survivin involves activation of the phosphatidylinositol-3-kinase (PI3K)/Akt pathway, which was antagonized by the PI3K-inhibitor, LY294002. Interestingly, application of the iNOS-inhibitor 1400W together with RNAi-mediated survivin down-regulation cooperatively enhanced drug-induced apoptosis in OCCs. The iNOS/survivin interdependencies seem to be also of clinical relevance because immunohistochemistry revealed that low iNOS levels correlate with survivin expression (P < 0.01) in carboplatin/paclitaxel-treated EOC patients with minimal postoperative residual tumor (n = 54). Also, iNOS and survivin expression were associated with increased risk for disease progression. Our study uncovers a novel molecular mechanism of how NO signaling may contribute to therapy resistance in EOC by modulating survivin expression. Pharmacogenetic iNOS/survivin-targeting strategies may hence be pursued to complement current treatment modalities in EOC.