Protein kinase C-alpha activity inversely modulates invasion and growth of intestinal cells.
The phorbol ester phorbol 12-myristate 13-acetate induces remarkable phenotypic changes in intestinal HT-29 M6 cells; these changes consist of loss of homotypic adhesion and inactivation of E-cadherin. In parallel, cell growth is retarded. We have transfected HT-29 M6 cells with an activated form of the conventional protein kinase Calpha (cPK-Calpha). Expression of this isoform induced the acquisition of a scattered phenotype, similar to that adopted by cells after addition of phorbol 12-myristate 13-acetate, with very low cell-to-cell aggregation and undetectable levels of functional E-cadherin. These cell clones were highly motile and rapidly invaded embryonic chick heart fragments. Furthermore, cells expressing activated-cPK-Calpha showed decreased proliferation in comparison to control clones. We have also studied how these two apparently antagonistic changes affect the tumorigenic ability of HT-29 M6 cells. When the different cell clones were xenografted into athymic mice, the effect on cell growth seemed to predominate. Expression of activated-cPK-Calpha significantly reduced the size of the tumors; the cells with the highest level of expression did not even form subcutaneous tumors. Besides their smaller size, the morphology of these tumors was clearly different from those originated by HT-29 M6 cells, and they could be defined as infiltrative on anatomo-pathological basis. These results indicate that cPK-Calpha controls both cell-to-cell adhesion and proliferation of intestinal cells.
Batlle
E
E
Unitat de Biologia Cel.lular i Molecular, Institut Municipal d'Investigació Mèdica, Calle Dr. Aiguader 80, 08003 Barcelona, Spain.
Verdú
J
J
Domínguez
D
D
del Mont Llosas
M
M
Díaz
V
V
Loukili
N
N
Paciucci
R
R
Alameda
F
F
de Herreros
A G
AG
D000818:Animals; D015820:Cadherins / Q000032:analysis; D002227:Carbazoles / Q000494:pharmacology; D002448:Cell Adhesion / Q000235:genetics*; D002465:Cell Movement / Q000235:genetics*; D048429:Cell Size / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D016297:Mutagenesis, Site-Directed / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000503:physiopathology*; D009374:Neoplasms, Experimental / Q000473:pathology; D011493:Protein Kinase C / Q000235:genetics / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D014162:Transfection / Q000235:genetics; D014183:Transplantation, Heterologous / Q000473:pathology; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000032:analysis
D015820:Cadherins; D002227:Carbazoles; D007211:Indoles; D008301:Maleimides; C081021:Go 6976; D011493:Protein Kinase C; D014568:Urokinase-Type Plasminogen Activator; C070515:bisindolylmaleimide I; D013755:Tetradecanoylphorbol Acetate