Radicicol induces intracellular accumulation of glycan-deficient clusterin variant

Proteostasis regulation using naturally occurring small molecules has been considered as a promising strategy for manipulating cancer sensitivity and therapy. Here, we identify a small molecule Hsp90 inhibitor radicicol that induces intracellular accumulation of cytotoxic clusterin variant. In the m...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 2015-03, Vol.458 (3), p.555-560
Main Authors: Choi, Ilho, Lee, Yumi, Park, Joong-Yeol, Song, Youngsup, Chang, Eun-Ju, Kang, Sang-Wook
Format: Article
Language:English
Subjects:
Cell Line, Tumor
Clusterin - metabolism
Endoplasmic Reticulum Stress - drug effects
Glycosylation - drug effects
HSP90 Heat-Shock Proteins - antagonists & inhibitors
HSP90 Heat-Shock Proteins - metabolism
Humans
Macrolides - pharmacology
Neoplasms - drug therapy
Neoplasms - metabolism
Protein Isoforms - metabolism
Protein Synthesis Inhibitors - pharmacology
Proteolysis - drug effects
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Summary:Proteostasis regulation using naturally occurring small molecules has been considered as a promising strategy for manipulating cancer sensitivity and therapy. Here, we identify a small molecule Hsp90 inhibitor radicicol that induces intracellular accumulation of cytotoxic clusterin variant. In the mechanistic basis, this variant proved to be a product disposed from the stressed ER. During this process, inhibitory effect of radicicol on protein degradation results in cytosolic accumulation of glycan-deficient clusterin variant that signals cell death. These results provide a therapeutic insight into the targeted proteostasis perturbation of clusterin as an anti-cancer strategy.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2015.02.005