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1000
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Abstract/Summary
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AUTHOR SUMMARY:
Cancer is still one of the leading causes of death in the Western world, and metastasis—the spread of cancer to distant sites—represents the most critical attribute for therapy failure. In colorectal cancer, up to one-third of patients have already developed metastasis at the time of diagnosis, and about half of newly diagnosed patients will develop metastasis during the course of the disease. MACC1 was first described as a key driver of metastasis formation in colorectal cancer, and its importance was later confirmed for other solid tumor entities. Stratification of patients with high MACC1 expression identifies patients at high risk of developing metastasis. Here we present a mechanism of targeting MACC1 as a potential therapy option for these high-risk patients. We identify the small molecules lovastatin and rottlerin as transcriptional inhibitors of MACC1. We describe the mechanism by which these molecules inhibit MACC1 expression and show that MACC1 inhibition leads to a reduced migratory phenotype in vitro and limits metastatic spread in preclinical mouse models. We propose repositioning of these 2 known drug molecules to reduce MACC1-driven metastasis formation in high-risk patients even before metastatic spread is clinically evident.
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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.
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