Restoration of full-length adenomatous polyposis coli (APC) protein in a colon cancer cell line enhances cell adhesion.
The APC tumour suppressor gene is mutated in most colon cancers. A major role of APC is the downregulation of the beta-catenin/T-cell factor (Tcf)/lymphoid enhancer factor (LEF) signalling pathway; however, there are also suggestions that it plays a role in the organization of the cytoskeleton, and in cell adhesion and migration. For the first time, we have achieved stable expression of wild-type APC in SW480 colon cancer cells, which normally express a truncated form of APC. The ectopically expressed APC is functional, and results in the translocation of beta-catenin from the nucleus and cytoplasm to the cell periphery, and reduces beta-catenin/Tcf/LEF transcriptional signalling. E-cadherin is also translocated to the cell membrane, where it forms functional adherens junctions. Total cellular levels of E-cadherin are increased in the SW480APC cells and the altered charge distribution in the presence of full-length APC suggests that APC is involved in post-translational regulation of E-cadherin localization. Changes in the location of adherens junction proteins are associated with tighter cell-cell adhesion in SW480APC cells, with consequent changes in cell morphology, the actin cytoskeleton and cell migration in a wound assay. SW480APC cells have a reduced proliferation rate, a reduced ability to form colonies in soft agar and do not grow tumours in a xenograft mouse tumour model. By regulating the intracellular transport of junctional proteins, we propose that APC plays a role in cell adhesion in addition to its known role in beta-catenin transcriptional signalling.
Faux
Maree C
MC
Ludwig Institute for Cancer Research, Parkville, Victoria 3050, Australia. maree.faux@ludwig.edu.au
Ross
Janine L
JL
Meeker
Clare
C
Johns
Terry
T
Ji
Hong
H
Simpson
Richard J
RJ
Layton
Meredith J
MJ
Burgess
Antony W
AW
D025601:Adenomatous Polyposis Coli Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D022005:Adherens Junctions / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology*; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism; D003110:Colonic Neoplasms / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1; D021381:Protein Transport; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured; D051176:beta Catenin
D025601:Adenomatous Polyposis Coli Protein; C495270:CTNNB1 protein, human; D015820:Cadherins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; D015534:Trans-Activators; D014157:Transcription Factors; D051176:beta Catenin