Protein kinase C alpha/beta inhibitor Go6976 promotes formation of cell junctions and inhibits invasion of urinary bladder carcinoma cells.
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 PKCalpha and PKCbeta isoenzymes, induced rapid clustering of cultured carcinoma cells and formation of an increased number of desmosomes and adherens junctions. Safingol, a PKCalpha inhibitor, had similar but less pronounced effects. In contrast, a PKCdelta 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 PKCalpha and beta isoenzymes induced translocation of beta1-integrin from the cell-matrix junctions and that beta4-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 PKCalpha/beta.
Department of Anatomy, University of Oulu, Oulu, Finland.
Jussi
J
Koivunen
Vesa
V
Aaltonen
Sanna
S
Koskela
Petri
P
Lehenkari
Matti
M
Laato
Juha
J
Peltonen
D000199:Actins / Q000378:metabolism; D022005:Adherens Junctions / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002227:Carbazoles / Q000494:pharmacology*; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003896:Desmosomes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007365:Intercellular Junctions / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009361:Neoplasm Invasiveness; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology
D000199:Actins; D002227:Carbazoles; D004791:Enzyme Inhibitors; D007211:Indoles; C081021:Go 6976; C496628:PRKCA protein, human; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha