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

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.

• Authors: Oksana Voloshanenko, Gerrit Erdmann, Taronish D Dubash, Iris Augustin, Marie Metzig, Giusi Moffa, Christian Hundsrucker, Grainne Kerr, Thomas Sandmann, Benedikt Anchang, Kubilay Demir, Christina Boehm, Svenja Leible, Claudia R Ball, Hanno Glimm, Rainer Spang, Michael Boutros
• Journal: Nature communications (Nat Commun) Vol. 4 Pg. 2610 ( 2013) ISSN: 2041-1723 [Electronic] England
• PMID: 24162018 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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