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Thein vitroeffects of H-89, a specific inhibitor of protein kinase A, in the human colo...
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Thein vitroeffects of H-89, a specific inhibitor of protein kinase A, in the human colonic carcinoma cell line Caco-2
作者:
S Böckmann,
B Nebe,
期刊:
European Journal of Cancer Prevention
(OVID Available online 2003)
卷期:
Volume 12,
issue 6
页码: 469-478
ISSN:0959-8278
年代: 2003
出版商: OVID
关键词: Apoptosis;Caco-2 cells;protein kinase A inhibitor H-89.
数据来源: OVID
摘要:
H-89 is a compound characterizedin vitroas a potent and selective inhibitor of protein kinase A. In the present study, we observed that H-89 induced morphological transformation and caused growth inhibition of the human colon cancer cell line Caco-2 in a dose-dependent manner. However, another protein kinase A inhibitor, H-8, had no effect on Caco-2 cells. To evaluate the possible molecular mechanism of H-89-evoked effects in Caco-2 cells, we analysed the capacity of H-89 to regulate the protein kinase B (Akt/PKB) signalling pathway. H-89 treatment led to an activation of Akt/PKB in Caco-2 cells. This activation was phosphatidylinositol 3 (PI3)-kinase-dependent and promoted survival of Caco-2 cells because the PI3 kinase inhibitor LY294002 inhibited the Akt/PKB activation and induced apoptosis of Caco-2 cells. To test whether Akt/PKB activity promoted resistance to H-89-induced effects, LY294002 was added in combination with H-89. LY294002 greatly potentiated the H-89-induced growth inhibition and apoptosis of Caco-2 cells. These results suggest that the H-89-induced growth inhibition of Caco-2 cells is associated with phosphorylation of Akt/PKB protein and that the cells become more sensitive to H-89 and die by apoptosis upon inhibition of the PI3K/Akt pathway.
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