The Biotechnology Centre of Oslo, University of Oslo , P.O. Box 1125 Blindern, 0317 Oslo, Norway.
J Proteome Res. 2012 Mar 2;11(3):1609-20. doi: 10.1021/pr200790e. Epub 2012 Feb 15.
Sorafenib is a multikinase inhibitor that is approved for use against renal cell and hepatocellular carcinoma. We found that sorafenib potently induced cell death in human neuroblastoma cells. To understand the molecular basis of sorafenib-mediated cell death in human SH-SY5Y cells, we performed a temporal quantitative proteome analysis. The results showed significant quantitative changes of 193 unique proteins. Bioinformatics-assisted pathway analysis of the regulated proteins revealed that mitochondrial proteins, especially components of the electron transport chain and the mitochondrial ribosomes, were significantly affected upon exposure to sorafenib. The observed down-regulation of the respiratory chain complex I (NADH dehydrogenase) was accompanied with loss of mitochondrial transmembrane potential (Δψm) and complete impairment of complex I enzyme activity. The destabilization of complex I subunits was consistent, rapid, and independent of caspase activation as well as Bcl-2 overexpression. This study provides an overview of the molecular machinery driving sorafenib-mediated cell death in neuroblastoma cells and suggests that sorafenib could be a potential therapeutic drug for the treatment of neuroblastoma.
索拉非尼是一种多激酶抑制剂，已被批准用于治疗肾细胞癌和肝细胞癌。我们发现索拉非尼能强烈诱导人神经母细胞瘤细胞死亡。为了了解索拉非尼介导的人 SH-SY5Y 细胞死亡的分子基础，我们进行了时间定量蛋白质组分析。结果显示 193 种独特蛋白质的含量有显著变化。对调控蛋白的生物信息学辅助途径分析表明，线粒体蛋白，特别是电子传递链和线粒体核糖体的成分，在暴露于索拉非尼后受到明显影响。观察到呼吸链复合物 I（NADH 脱氢酶）的下调伴随着线粒体跨膜电位（Δψm）的丧失和复合物 I 酶活性的完全丧失。复合物 I 亚基的不稳定性是一致的、快速的，并且与 caspase 激活以及 Bcl-2 过表达无关。本研究概述了驱动神经母细胞瘤细胞中索拉非尼介导的细胞死亡的分子机制，并表明索拉非尼可能是治疗神经母细胞瘤的潜在治疗药物。
