Ignashkova Tatiana I, Gendarme Mathieu, Peschk Katrin, Eggenweiler Hans-Michael, Lindemann Ralph K, Reiling Jan H
Metabolism and Signaling in Cancer, BioMed X Innovation Center, Heidelberg, Germany.
Medicinal Chemistry, Merck Biopharma, Merck KGaA, Darmstadt, Germany.
Traffic. 2017 Aug;18(8):530-544. doi: 10.1111/tra.12493. Epub 2017 Jun 30.
The Golgi apparatus is part of the secretory pathway and of central importance for modification, transport and sorting of proteins and lipids. ADP-ribosylation factors, whose activation can be blocked by brefeldin A (BFA), play a major role in functioning of the Golgi network and regulation of membrane traffic and are also involved in proliferation and migration of cancer cells. Due to high cytotoxicity and poor bioavailability, BFA has not passed the preclinical stage of drug development. Recently, AMF-26 and golgicide A have been described as novel inhibitors of the Golgi system with antitumor or bactericidal properties. We provide here further evidence that AMF-26 closely mirrors the mode of action of BFA but is less potent. Using several human cancer cell lines, we studied the effects of AMF-26, BFA and golgicide A on cell homeostasis including Golgi structure, endoplasmic reticulum (ER) stress markers, secretion and viability, and found overall a significant correlation between these parameters. Furthermore, modulation of ADP-ribosylation factor expression has a profound impact on Golgi organization and survival in response to Golgi stress inducers.
高尔基体是分泌途径的一部分，对于蛋白质和脂质的修饰、运输和分选至关重要。ADP核糖基化因子的激活可被布雷菲德菌素A（BFA）阻断，在高尔基体网络功能以及膜运输调节中起主要作用，还参与癌细胞的增殖和迁移。由于细胞毒性高和生物利用度差，BFA尚未通过药物开发的临床前阶段。最近，AMF-26和高尔基体杀虫剂A被描述为具有抗肿瘤或杀菌特性的新型高尔基体系统抑制剂。我们在此提供进一步证据，表明AMF-26与BFA的作用模式非常相似，但效力较弱。使用几种人类癌细胞系，我们研究了AMF-26、BFA和高尔基体杀虫剂A对细胞稳态的影响，包括高尔基体结构、内质网（ER）应激标志物、分泌和活力，发现这些参数之间总体存在显著相关性。此外，ADP核糖基化因子表达的调节对高尔基体组织和应对高尔基体应激诱导剂时的存活有深远影响。
