Cell survival and protein secretion associated with Golgi integrity in response to Golgi stress‐inducing agents. (30th June 2017)

• Record Type: Journal Article
• Authors: Ignashkova, Tatiana I.; Gendarme, Mathieu; Peschk, Katrin; Eggenweiler, Hans‐Michael; Lindemann, Ralph K.; Reiling, Jan H.
• Is Part Of: Traffic. Volume 18:Number 8(2017)
• Page Start: 530
• Page End: 544
• Publication Date: 2017-06-30
• Subjects: AMF‐26 -- ARF GTPase -- brefeldin A -- Golgi fragmentation -- Golgi stress -- golgicide A; Biological transport -- Periodicals; 571.6
• DOI: 10.1111/tra.12493
• Languages: English
• ISSNs: 1398-9219

Abstract

Abstract : 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. Abstract : The small molecules AMF‐26, brefeldin A (BFA) and golgicide A (GCA) are inhibitors of protein trafficking and cause Golgi complex disintegration. We show here that AMF‐26 has a comparable mechanism of action to BFA but is less potent. Modulation of ARF GTPase isoform levels, in particular ARF1 and ARF5, critically impact cell survival and Golgi morphology in response to Golgi stressors. Furthermore, a significant association of AMF‐26‐, BFA‐ or GCA‐mediated Golgi dispersal, cell survival and protein secretion is revealed .