Liu Yanxia, Law Brian K, Luesch Hendrik
Department of Medicinal Chemistry, University of Florida, Gainesville, FL 32610, USA.
Mol Pharmacol. 2009 Jul;76(1):91-104. doi: 10.1124/mol.109.056085. Epub 2009 Apr 29.
Apratoxin A is a potent cytotoxic marine natural product that rapidly inhibits signal transducer and activator of transcription (STAT) 3 phosphorylation by an undefined mechanism. We have used biochemical and proteomics approaches to illuminate upstream molecular events. Apratoxin A inhibits Janus kinase (JAK)/STAT signaling through rapid down-regulation of interleukin 6 signal transducer (gp130). Apratoxin A also depletes cancer cells of several cancer-associated receptor tyrosine kinases by preventing their N-glycosylation, leading to their rapid proteasomal degradation. A proteomics approach revealed that several proteins in the endoplasmic reticulum, the site of N-glycoprotein synthesis, are down-regulated upon apratoxin A exposure. Using in vitro cell free systems, we demonstrated that apratoxin A prevents cotranslational translocation of proteins destined for the secretory pathway. This process is reversible in living cells. Our study indicates that apratoxins are new tools to study the secretory pathway and raises the possibility that inhibition of cotranslational translocation may be exploited for anticancer drug development.
阿普拉毒素A是一种强效的细胞毒性海洋天然产物，它能通过一种不明机制迅速抑制信号转导子和转录激活子（STAT）3的磷酸化。我们已采用生化和蛋白质组学方法来阐明上游分子事件。阿普拉毒素A通过快速下调白细胞介素6信号转导子（gp130）来抑制Janus激酶（JAK）/STAT信号通路。阿普拉毒素A还通过阻止几种癌症相关受体酪氨酸激酶的N-糖基化，使其从癌细胞中耗竭，导致它们迅速被蛋白酶体降解。蛋白质组学方法显示，N-糖蛋白合成位点内质网中的几种蛋白质在暴露于阿普拉毒素A后表达下调。利用体外无细胞系统，我们证明阿普拉毒素A可阻止分泌途径中蛋白质的共翻译转运。这一过程在活细胞中是可逆的。我们的研究表明，阿普拉毒素是研究分泌途径的新工具，并增加了一种可能性，即抑制共翻译转运可用于抗癌药物开发。
