Wnt secretion is required to maintain high levels of Wnt activity in colon cancer cells

Nat Commun. 2013;4:2610. doi: 10.1038/ncomms3610.

Abstract

Aberrant regulation of the Wnt/β-catenin pathway has an important role during the onset and progression of colorectal cancer, with over 90% of cases of sporadic colon cancer featuring mutations in APC or β-catenin. However, it has remained a point of controversy whether these mutations are sufficient to activate the pathway or require additional upstream signals. Here we show that colorectal tumours express elevated levels of Wnt3 and Evi/Wls/GPR177. We found that in colon cancer cells, even in the presence of mutations in APC or β-catenin, downstream signalling remains responsive to Wnt ligands and receptor proximal signalling. Furthermore, we demonstrate that truncated APC proteins bind β-catenin and key components of the destruction complex. These results indicate that cells with mutations in APC or β-catenin depend on Wnt ligands and their secretion for a sufficient level of β-catenin signalling, which potentially opens new avenues for therapeutic interventions by targeting Wnt secretion via Evi/Wls.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics*
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Adenomatous Polyposis Coli Protein / genetics*
  • Adenomatous Polyposis Coli Protein / metabolism
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation
  • Colon / metabolism
  • Colon / pathology
  • Colonic Neoplasms / genetics*
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mice
  • Mice, Inbred NOD
  • Mutation
  • Neoplasm Transplantation
  • Receptor, EphB2 / genetics
  • Receptor, EphB2 / metabolism
  • Receptors, G-Protein-Coupled / genetics*
  • Receptors, G-Protein-Coupled / metabolism
  • Signal Transduction
  • Wnt3 Protein / genetics*
  • Wnt3 Protein / metabolism
  • beta Catenin / genetics*
  • beta Catenin / metabolism

Substances

  • APC protein, human
  • Adenomatous Polyposis Coli Protein
  • CTNNB1 protein, human
  • GPR177 protein, human
  • Intracellular Signaling Peptides and Proteins
  • Receptors, G-Protein-Coupled
  • WNT3 protein, human
  • Wnt3 Protein
  • beta Catenin
  • EPHB2 protein, human
  • Receptor, EphB2