Apratoxin a reversibly inhibits the secretory pathway by preventing cotranslational translocation.
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.
Liu
Yanxia
Y
Department of Medicinal Chemistry, University of Florida, Gainesville, FL 32610, USA.
Law
Brian K
BK
Luesch
Hendrik
H
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050822:Cytokine Receptor gp130 / Q000502:physiology; D047630:Depsipeptides / Q000494:pharmacology*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D014176:Protein Biosynthesis / Q000187:drug effects*; D021381:Protein Transport / Q000187:drug effects; D040901:Proteomics; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D014415:Tunicamycin / Q000494:pharmacology
D047630:Depsipeptides; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C442201:apratoxin A; D014415:Tunicamycin; D050822:Cytokine Receptor gp130