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Statin and rottlerin small-molecule inhibitors restrict colon cancer progression and metastasis via MACC1

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Item Type:Article
Title:Statin and rottlerin small-molecule inhibitors restrict colon cancer progression and metastasis via MACC1
Creators Name:Juneja, M. and Kobelt, D. and Walther, W. and Voss, C. and Smith, J. and Specker, E. and Neuenschwander, M. and Gohlke, B.O. and Dahlmann, M. and Radetzki, S. and Preissner, R. and von Kries, J.P. and Schlag, P.M. and Stein, U.
Abstract:MACC1 (Metastasis Associated in Colon Cancer 1) is a key driver and prognostic biomarker for cancer progression and metastasis in a large variety of solid tumor types, particularly colorectal cancer (CRC). However, no MACC1 inhibitors have been identified yet. Therefore, we aimed to target MACC1 expression using a luciferase reporter-based high-throughput screening with the ChemBioNet library of more than 30,000 compounds. The small molecules lovastatin and rottlerin emerged as the most potent MACC1 transcriptional inhibitors. They remarkably inhibited MACC1 promoter activity and expression, resulting in reduced cell motility. Lovastatin impaired the binding of the transcription factors c-Jun and Sp1 to the MACC1 promoter, thereby inhibiting MACC1 transcription. Most importantly, in CRC-xenografted mice, lovastatin and rottlerin restricted MACC1 expression and liver metastasis. This is-to the best of our knowledge-the first identification of inhibitors restricting cancer progression and metastasis via the novel target MACC1. This drug repositioning might be of therapeutic value for CRC patients.
Keywords:Acetophenones, Antineoplastic Agents, Benzopyrans, Binding Sites, Cell Proliferation, Colorectal Neoplasms, Experimental Liver Neoplasms, Genetic Promoter Regions, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Molecular Docking Simulation, Neoplasm Proteins, Neoplastic Gene Expression Regulation, Random Allocation, Recombinant Proteins, Reporter Genes, SCID Mice, Small Molecule Libraries, Transcription Factors, Tumor Burden, Tumor Cell Line, Uncoupling Agents, Xenograft Model Antitumor Assays, Animals, Mice
Source:PLoS Biology
ISSN:1545-7885
Publisher:Public Library of Science (U.S.A.)
Volume:15
Number:6
Page Range:e2000784
Date:1 June 2017
Official Publication:https://doi.org/10.1371/journal.pbio.2000784
PubMed:View item in PubMed

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