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First published online 16 December 2003
doi: 10.1242/jcs.00862
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Research Article |
1 Ludwig Institute for Cancer Research, Ludwig Institute for Cancer Research and Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia
2 Joint ProteomicS Laboratory, Ludwig Institute for Cancer Research and Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia
3 CRC for Cellular Growth Factors, Ludwig Institute for Cancer Research and Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia
* Author for correspondence (e-mail: maree.faux{at}ludwig.edu.au)
Accepted 9 September 2003
The APC tumour suppressor gene is mutated in most colon cancers. A major role of APC is the downregulation of the ß-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 ß-catenin from the nucleus and cytoplasm to the cell periphery, and reduces ß-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 ß-catenin transcriptional signalling.
Key words: APC, ß-catenin, Colon cancer cells, E-cadherin, Tumour suppressor gene
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