An image-based small-molecule screen identifies vimentin as a pharmacologically relevant target of simvastatin in cancer cells

Trogden KP, Battaglia RA, Kabiraj P, Madden VJ, Herrmann H, Snider NT (2018)

Publication Type: Journal article

Publication year: 2018

Journal

The FASEB Journal Federation of American Society of Experimental Biology (FASEB)

Book Volume: 32

Pages Range: 2841-2854

Journal Issue: 5

DOI: 10.1096/fj.201700663R

Abstract

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 µM, 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.-Trogden, K. P., Battaglia, R. A., Kabiraj, P., Madden, V. J., Herrmann, H., Snider, N. T. An image-based small-molecule screen identifies vimentin as a pharmacologically relevant target of simvastatin in cancer cells.

Additional Organisation(s)

Institute of Neuropathology

Involved external institutions

University of North Carolina at Chapel Hill US United States (USA) (US) Deutsches Krebsforschungszentrum (DKFZ) DE Germany (DE)

How to cite

APA:

Trogden, K.P., Battaglia, R.A., Kabiraj, P., Madden, V.J., Herrmann, H., & Snider, N.T. (2018). An image-based small-molecule screen identifies vimentin as a pharmacologically relevant target of simvastatin in cancer cells. The FASEB Journal, 32(5), 2841-2854. https://dx.doi.org/10.1096/fj.201700663R

MLA:

Trogden, Kathryn P., et al. "An image-based small-molecule screen identifies vimentin as a pharmacologically relevant target of simvastatin in cancer cells." The FASEB Journal 32.5 (2018): 2841-2854.

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