Odoroside A and ouabain inhibit Na+/K+-ATPase and prevent NF-kappaB-inducible protein expression by blocking Na+-dependent amino acid transport.
Odoroside A and ouabain inhibit Na+/K+-ATPase and prevent NF-kappaB-inducible protein expression by blocking Na+-dependent amino acid transport.
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DOI：
10.1016/j.bcp.2009.06.027
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发表时间：
2009-11
影响因子：
5.8
通讯作者：
Yohei Takada;K. Matsuo;H. Ogura;L. Bai;A. Toki;Liyan Wang;M. Ando;T. Kataoka
中科院分区：
文献类型：
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作者：
Yohei Takada;K. Matsuo;H. Ogura;L. Bai;A. Toki;Liyan Wang;M. Ando;T. Kataoka
炎性细胞因子，如肿瘤坏死因子（TNF）-α和白细胞介素-1（IL-1），触发转录因子NF-κB的活化，从而诱导多种基因的表达，包括细胞间粘附分子（ICAM）-1。3β-O-（β-d-diginosyl）-14-hydroxy-5β，14 β-card-20（22）-englands [3β-O-（β-d-diginosyl）-14-hydroxy-5β，14 β-card-20（22）-englands]能抑制TNF-α和IL-1诱导的人肺癌A549细胞表面ICAM-1的表达。本研究进一步探讨了odoroside A与Na+/K+-ATP酶特异性抑制剂哇巴因联合抑制TNF-α诱导的细胞表面ICAM-1表达的分子机制。Odoroside A和ouabain既不能阻止IκBα降解，也不能阻止NF-κB易位到细胞核。而苦豆甙A和哇巴因对TNF-α诱导的ICAM-1 mRNA表达无抑制作用，但在蛋白水平上抑制TNF-α诱导的ICAM-1表达。与这些结果一致，odoroside A和哇巴因有效地减少从头蛋白质合成，这主要是由于其能够阻断Na+依赖的氨基酸跨质膜转运，但不干扰翻译机制。作为一个直接的分子靶点，odoroside A对Na ~+/K ~+-ATP酶的ATP水解活性具有与哇巴因相当的抑制作用。这些结果清楚地表明，odoroside A和哇巴因通过阻断Na+依赖的氨基酸转运来阻止NF-κ B诱导的蛋白表达。
Inflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin-1 (IL-1), trigger the activation of transcription factor NF-κB that induces the expression of a variety of genes, including intercellular adhesion molecule (ICAM)-1. Odoroside A [3β-O-(β-d-diginosyl)-14-hydroxy-5β,14β-card-20(22)-enolide] was found to inhibit the cell-surface expression of ICAM-1 induced by TNF-α and IL-1 at comparable concentrations in human lung carcinoma A549 cells. In this study, the molecular mechanism underlying the inhibition of TNF-α-induced cell-surface ICAM-1 expression by odoroside A together with the specific Na+/K+-ATPase inhibitor ouabain was further investigated. Odoroside A and ouabain neither prevented IκBα degradation nor NF-κB translocation to the nucleus upon TNF-α stimulation. While odoroside A and ouabain had no inhibitory effect on the induction of ICAM-1 mRNA, they inhibited the TNF-α-induced ICAM-1 expression at the protein level. Consistent with these results, odoroside A and ouabain potently reduced de novo protein synthesis, largely due to its ability to block Na+-dependent transport of amino acids across the plasma membrane, but not to interfering with the translation machinery. As a direct molecular target, odoroside A was found to inhibit the ATP-hydrolyzing activity of Na+/K+-ATPase as potently as ouabain. These results clearly demonstrate that odoroside A and ouabain prevent NF-κB-inducible protein expression by blocking the Na+-dependent amino acid transport.