期刊
FASEB JOURNAL
卷 32, 期 5, 页码 2841-2854出版社
WILEY
DOI: 10.1096/fj.201700663R
关键词
statin; intermediate filaments; cytoskeleton; drug screen
资金
- Department of Cell Biology and Physiology at the University of North Carolina-Chapel Hill
- National Science Foundation Graduate Research Fellowship
- U.S. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases Grant [R01-DK110355]
Vimentin is a cytoskeletal intermediate filament protein that is expressed in mesenchymal cells and cancer cells during the epithelial-mesenchymal transition. The goal of this study was to identify vimentin-targeting small molecules by using the Tocriscreen library of 1120 biochemically active compounds. We monitored vimentin filament reorganization and bundling in adrenal carcinoma SW13 vimentin-positive (SW13-vim(+) cells via indirect immunofluorescence. The screen identified 18 pharmacologically diverse hits that included 2 statins-simvastatin and mevastatin. Simvastatin induced vimentin reorganization within 15-30 min and significant perinuclear bundling within 60 min (IC50 = 6.7 nM). Early filament reorganization coincided with increased vimentin solubility. Mevastatin produced similar effects at >1 mu M, whereas the structurally related pravastatin and lovastatin did not affect vimentin. In vitro vimentin filament assembly assays revealed a direct targeting mechanism, as determined biochemically and by electron microscopy. In SW13-vim(+) cells, simvastatin, but not pravastatin, reduced total cell numbers (IC50 = 48.1 nM) and promoted apoptosis after 24 h. In contrast, SW13-vim(-) cell viability was unaffected by simvastatin, unless vimentin was ectopically expressed. Simvastatin similarly targeted vimentin filaments and induced cell death in MDA-MB-231 (vim(+)), but lacked effect in MCF7 (vim(-)) breast cancer cells. In conclusion, this study identified vimentin as a direct molecular target that mediates simvastatin-induced cell death in 2 different cancer cell lines.
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