Suppression of colon cancer metastasis by Aes through inhibition of Notch signaling

Cancer Cell. 2011 Jan 18;19(1):125-37. doi: 10.1016/j.ccr.2010.11.008.

Abstract

Metastasis is responsible for most cancer deaths. Here, we show that Aes (or Grg5) gene functions as an endogenous metastasis suppressor. Expression of Aes was decreased in liver metastases compared with primary colon tumors in both mice and humans. Aes inhibited Notch signaling by converting active Rbpj transcription complexes into repression complexes on insoluble nuclear matrix. In tumor cells, Notch signaling was triggered by ligands on adjoining blood vessels, and stimulated transendothelial migration. Genetic depletion of Aes in Apc(Δ716) intestinal polyposis mice caused marked tumor invasion and intravasation that were suppressed by Notch signaling inhibition. These results suggest that inhibition of Notch signaling can be a promising strategy for prevention and treatment of colon cancer metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzodiazepinones / pharmacology
  • Benzodiazepinones / therapeutic use
  • Cell Line, Tumor
  • Co-Repressor Proteins
  • Colonic Neoplasms / drug therapy
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology*
  • Down-Regulation / genetics
  • Gene Expression / genetics
  • Gene Silencing / physiology
  • HCT116 Cells
  • Humans
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein / genetics
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein / metabolism
  • Intestinal Polyposis / drug therapy
  • Intestinal Polyposis / metabolism
  • Intestinal Polyposis / pathology
  • Ligands
  • Liver Neoplasms / pathology
  • Liver Neoplasms / secondary
  • Lung Neoplasms / pathology
  • Lung Neoplasms / prevention & control
  • Lung Neoplasms / secondary
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Mice, Nude
  • Mice, Transgenic
  • Models, Biological
  • Neoplasm Invasiveness / genetics
  • Neoplasm Invasiveness / pathology
  • Neoplasm Invasiveness / prevention & control
  • Neoplasm Metastasis / genetics
  • Neoplasm Metastasis / pathology
  • Neoplasm Metastasis / prevention & control
  • Nuclear Matrix / metabolism
  • Receptor, Notch1 / metabolism
  • Receptors, Notch / antagonists & inhibitors
  • Receptors, Notch / metabolism*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Stromal Cells / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transendothelial and Transepithelial Migration / physiology

Substances

  • 2-(((3,5-difluorophenyl)acetyl)amino)-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl)propanamide
  • Benzodiazepinones
  • Co-Repressor Proteins
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein
  • Ligands
  • Notch1 protein, mouse
  • Rbpj protein, mouse
  • Receptor, Notch1
  • Receptors, Notch
  • Repressor Proteins
  • TLE5 protein, human
  • Tle1 protein, mouse
  • Tle5 protein, mouse
  • Transcription Factors

Associated data

  • GEO/GSE12162