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-Catenin-negative Human Colon Cancer Cell Variants via
Induction of Desmosomes
* Department of Molecular Biology, Laboratory of Molecular Cell Biology, University of Ghent and Flanders Interuniversity
Institute of Biotechnology (V.I.B.), B-9000 Ghent; The Our studies show that it is possible to bypass the need
for normal University Hospital Ghent, Department of Radiotherapy, Nuclear Medicine
and Experimental Cancerology, B-9000 Ghent; and § Department of Anatomy, Embryology, and Histology, University of Ghent,
B-9000 Ghent, Belgium
-catenin molecule links E-cadherin/
-catenin or E-cadherin/plakoglobin complexes to the
actin cytoskeleton. We studied several invasive human
colon carcinoma cell lines lacking -catenin. They
showed a solitary and rounded morphotype that correlated with increased invasiveness. These round cell
variants acquired a more normal epithelial phenotype
upon transfection with an -catenin expression plasmid, but also upon treatment with the protein kinase C
(PKC) activator 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Video registrations showed that the cells
started to establish elaborated intercellular junctions
within 30 min after addition of TPA. Interestingly, this
normalizing TPA effect was not associated with -catenin induction. Classical and confocal immunofluorescence showed only minor TPA-induced changes in
E-cadherin staining. In contrast, desmosomal and tight
junctional proteins were dramatically rearranged, with
a conversion from cytoplasmic clusters to obvious concentration at cell-cell contacts and exposition at the exterior cell surface. Electron microscopical observations
revealed the TPA-induced appearance of typical desmosomal plaques. TPA-restored cell-cell adhesion was
E-cadherin dependent as demonstrated by a blocking
antibody in a cell aggregation assay. Addition of an antibody against the extracellular part of desmoglein-2
blocked the TPA effect, too. Remarkably, the combination of anti-E-cadherin and anti-desmoglein antibodies
synergistically inhibited the TPA effect.
-catenin expression to establish tight intercellular adhesion by epithelial cells. Apparently, the
underlying mechanism comprises upregulation of desmosomes and tight junctions by activation of the PKC
signaling pathway, whereas E-cadherin remains essential for basic cell-cell adhesion, even in the absence of
-catenin.
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