Protein kinase C α/β inhibitor Go6976 promotes formation of cell junctions and inhibits invasion of urinary bladder carcinoma cells

被引:86
作者
Koivunen, J
Aaltonen, V
Koskela, S
Lehenkari, P
Laato, M
Peltonen, J
机构
[1] Univ Oulu, Dept Anat & Cell Biol, Oulu 90014, Finland
[2] Univ Oulu, Dept Dermatol, Oulu 90014, Finland
[3] Univ Oulu, Dept Surg, Clin Res Ctr, Oulu 90014, Finland
[4] Turku Univ, Cent Hosp, Dept Surg, FIN-20520 Turku, Finland
[5] Univ Turku, Dept Med Biochem, FIN-20520 Turku, Finland
关键词
D O I
10.1158/0008-5472.CAN-03-3511
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 13 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.
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收藏
页码:5693 / 5701
页数:9
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