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

PLoS Biol. 2017 Jun 1;15(6):e2000784. doi: 10.1371/journal.pbio.2000784. eCollection 2017 Jun.

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.

Publication types

  • Comparative Study

MeSH terms

  • Acetophenones / adverse effects
  • Acetophenones / chemistry
  • Acetophenones / pharmacology
  • Acetophenones / therapeutic use*
  • Animals
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Benzopyrans / adverse effects
  • Benzopyrans / chemistry
  • Benzopyrans / pharmacology
  • Benzopyrans / therapeutic use*
  • Binding Sites
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Genes, Reporter / drug effects
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / chemistry
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use*
  • Liver Neoplasms, Experimental / prevention & control
  • Liver Neoplasms, Experimental / secondary
  • Mice, SCID
  • Molecular Docking Simulation
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / chemistry
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism
  • Promoter Regions, Genetic / drug effects
  • Random Allocation
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Small Molecule Libraries
  • Trans-Activators
  • Transcription Factors / antagonists & inhibitors*
  • Transcription Factors / chemistry
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Tumor Burden / drug effects
  • Uncoupling Agents / adverse effects
  • Uncoupling Agents / chemistry
  • Uncoupling Agents / pharmacology
  • Uncoupling Agents / therapeutic use*
  • Xenograft Model Antitumor Assays

Substances

  • Acetophenones
  • Antineoplastic Agents
  • Benzopyrans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • MACC1 protein, human
  • Neoplasm Proteins
  • Recombinant Proteins
  • Small Molecule Libraries
  • Trans-Activators
  • Transcription Factors
  • Uncoupling Agents
  • rottlerin

Grants and funding

Helmholtz Alliance Preclinical Comprehensive Cancer Center https://www.helmholtz.de/en/about_us/networks_and_cooperation/helmholtz_alliances/pccc/. Received by US. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Helmholtz-Graduate School Molecular Cell Biology https://www.mdc-berlin.de/34793331/de/training/phd_program/Graduate-School. Received by MJ. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. German Cancer Consortium http://www.dktk-dkfz.de/en/home. Received by US and PMS. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.