Protein kinase C α/β inhibitor Go6976 promotes formation of cell junctions and inhibits invasion of urinary bladder carcinoma cells
Protein kinase C α/β inhibitor Go6976 promotes formation of cell junctions and inhibits invasion of urinary bladder carcinoma cells
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DOI：
10.1158/0008-5472.can-03-3511
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发表时间：
2004-08-15
期刊：
影响因子：
11.2
通讯作者：
Peltonen, J
中科院分区：
文献类型：
--
作者：
Koivunen, J;Aaltonen, V;Peltonen, J
不同蛋白激酶C （PKC）同工酶激活平衡的变化与癌症的发展有关。本研究探讨了不同PKC抑制剂对培养的高级别膀胱癌细胞（5637和T24）细胞接触的影响。将细胞暴露于同工酶特异性PKC抑制剂中产生了不同的结果：Go6976， PKCalpha和PKCbeta同工酶的抑制剂，诱导培养的癌细胞快速聚集，并形成更多的桥粒和粘附连接。一种PKCalpha抑制剂Safingol也有类似的效果，但效果不那么明显。相比之下，PKCdelta抑制剂rottlerin对细胞聚集具有相反的作用，并引起细胞连接的解离。广谱PKC抑制剂双吲哚酰马来酰亚胺I对培养物的形态或细胞连接的数量没有任何明显的影响。对Go6976的进一步研究表明，抑制PKCalpha和13个同工酶诱导β -整合素从细胞-基质连接处易位，β -整合素向培养基质转移。Go6976还能有效抑制癌细胞的迁移和通过人工基底膜的侵袭。我们对膀胱癌细胞的研究结果强调，由于Go6976对细胞-细胞和细胞-基质连接、迁移和侵袭的影响，它是一种潜在的抗癌药物。此外，这一结果可能与PKCalpha/ β抑制促进PKC激活平衡的变化有关。
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.