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

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

doi:10.1038/ncomms3610

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

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

Authors

Oksana Voloshanenko¹, 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

Affiliation

¹ 1] German Cancer Research Center (DKFZ), Div. Signalling and Functional Genomics, and Heidelberg University, Dept. Cell and Molecular Biology, Faculty of Medicine Mannheim, Im Neuenheimer Feld 580, D-69120 Heidelberg, Germany [2].

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
Intracellular Signaling Peptides and Proteins
Receptors, G-Protein-Coupled
WLS protein, human
WNT3 protein, human
Wnt3 Protein
beta Catenin
EPHB2 protein, human
Receptor, EphB2