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 k...

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Bibliographic Details
Published in:Molecular pharmacology 2009-07, Vol.76 (1), p.91-104
Main Authors: Liu, Yanxia, Law, Brian K, Luesch, Hendrik
Format: Article
Language:English
Subjects:
Cell Line, Tumor
Cell Proliferation - drug effects
Cytokine Receptor gp130 - physiology
Depsipeptides - pharmacology
Endoplasmic Reticulum - metabolism
Glycosylation
Humans
Protein Biosynthesis - drug effects
Protein Transport - drug effects
Proteomics
Signal Transduction - drug effects
STAT3 Transcription Factor - antagonists & inhibitors
STAT3 Transcription Factor - physiology
Tunicamycin - pharmacology
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Summary: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.
ISSN:0026-895X
1521-0111
DOI:10.1124/mol.109.056085