Nitric oxide mediates natural polyphenol-induced Bcl-2 down-regulation and activation of cell death in metastatic B16 melanoma
Nitric oxide mediates natural polyphenol-induced Bcl-2 down-regulation and activation of cell death in metastatic B16 melanoma
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DOI：
10.1074/jbc.m605934200
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发表时间：
2007-02-02
影响因子：
4.8
通讯作者：
Estrela, Jose M.
中科院分区：
文献类型：
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作者：
Ferrer, Paula;Asensi, Miguel;Estrela, Jose M.
向小鼠静脉内施用反式紫檀芪（t-PTER; 3，5-二甲氧基-4 '-羟基芪）和槲皮素（QUER; 3，3'，4 '，5，6-五羟基黄酮）（两种结构相关且天然存在的小多酚）抑制高度恶性B16黑素瘤F10（B16 M-F10）细胞的转移性生长。t-PTER和QUER抑制转移细胞中的bcl-2表达，这使它们对血管内皮诱导的细胞毒性敏感。然而，连接多酚信号传导和bcl-2表达的分子机制尚不清楚。NO是一种潜在的细胞凋亡生物调节剂，对Bcl-2的调节作用存在争议。多酚类物质可能影响NO的生成。短期（60分钟/天）暴露于t-PTER（40 μ M）和QUER（20 μ M）（静脉内给予每种多酚20 mg/kg后第一小时内测量的血浆浓度的近似平均值）下调B16 M-F10细胞中的诱导型NO合成酶，上调血管内皮中的内皮型NO合成酶，从而促进内皮诱导的肿瘤细胞毒性。极低和高浓度NO均下调B16 M-F10细胞bcl-2的表达。在B16 M-F10细胞中，t-PTER和QUER诱导cAMP反应元件结合蛋白磷酸化的NO短缺依赖性降低，cAMP反应元件结合蛋白磷酸化是bcl-2表达的正调节因子。另一方面，在癌症和内皮细胞相互作用期间，t-PTER和QUER诱导血管内皮释放NO，上调B16 M-F10细胞中性鞘磷脂酶活性和神经酰胺产生。直接NO诱导的细胞毒性和神经酰胺诱导的线粒体通透性转换和凋亡激活可以解释Bcl-2缺失的B16 M-F10细胞的内皮诱导的死亡增加。
Intravenous administration to mice of trans-pterostilbene (t-PTER; 3,5-dimethoxy-4'-hydroxystilbene) and quercetin (QUER; 3,3',4',5,6-pentahydroxyflavone), two structurally related and naturally occurring small polyphenols, inhibits metastatic growth of highly malignant B16 melanoma F10 (B16M-F10) cells. t-PTER and QUER inhibit bcl-2 expression in metastatic cells, which sensitizes them to vascular endothelium-induced cytotoxicity. However, the molecular mechanism(s) linking polyphenol signaling and bcl-2 expression are unknown. NO is a potential bioregulator of apoptosis with controversial effects on Bcl-2 regulation. Polyphenols may affect NO generation. Short-term exposure (60 min/day) to t-PTER (40 mu M) and QUER (20 mu M) (approximate mean values of the plasma concentrations measured within the first hour after intravenous administration of 20 mg of each polyphenol/kg) down-regulated inducible NO synthetase in B16M-F10 cells and up-regulated endothelial NO synthetase in the vascular endothelium and thereby facilitated endothelium-induced tumor cytotoxicity. Very low and high NO levels down-regulated bcl-2 expression in B16M-F10 cells. t-PTER and QUER induced a NO shortage-dependent decrease in cAMP-response element-binding protein phosphorylation, a positive regulator of bcl-2 expression, inB16M-F10 cells. On the other hand, during cancer and endothelial cell interaction, t-PTER- and QUER-induced NO release from the vascular endothelium up-regulated neutral sphingomyelinase activity and ceramide generation in B16M-F10 cells. Direct NO-induced cytotoxicity and ceramide-induced mitochondrial permeability transition and apoptosis activation can explain the increased endothelium-induced death of Bcl-2-depleted B16M-F10 cells.