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Protein Kinase C /ß Inhibitor Go6976 Promotes Formation of Cell Junctions and Inhibits Invasion of Urinary Bladder Carcinoma Cells

Departments of ¹ Anatomy and Cell Biology and ² Dermatology, University of Oulu, Oulu, Finland; ³ Department of Surgery, Clinical Research Center, University of Oulu, Oulu, Finland; ⁴ Department of Surgery, Turku University Central Hospital, Turku, Finland; and ⁵ Department of Medical Biochemistry, University of Turku, Turku, Finland

Changes in activation balance of different protein kinase C (PKC) isoenzymes have been linked to cancer development. The current study investigated the effect of different PKC inhibitors on cellular contacts in cultured high-grade urinary bladder carcinoma cells (5637 and T24). Exposure of the cells to isoenzyme-specific PKC inhibitors yielded variable results: Go6976, an inhibitor of PKC and PKCß isoenzymes, induced rapid clustering of cultured carcinoma cells and formation of an increased number of desmosomes and adherens junctions. Safingol, a PKC inhibitor, had similar but less pronounced effects. In contrast, a PKC inhibitor, rottlerin, had an opposite effect on cell clustering and caused dissociation of cell junctions. A broad-spectrum PKC inhibitor bisindolylmaleimide I did not have any apparent effect on the morphology of the cultures or on the number of cell junctions. Additional studies with Go6976 demonstrated that inhibition of PKC and ß isoenzymes induced translocation of ß1-integrin from the cell-matrix junctions and that ß4-integrin was translocated to face the culture substratum. Go6976 was also highly effective in inhibiting migration of carcinoma cells and inhibited invasion through artificial basement membrane. Our results on urinary bladder carcinoma cells emphasize that Go6976 is a potential anticancer drug due to its effects on cell-cell and cell-matrix junctions, migration, and invasion. Furthermore, the results may be explained by changes in PKC activation balance promoted by inhibition of PKC/ß.

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