Research papersThe in vitro effects of H-89, a specific inhibitor of protein kinase A, in the human colonic carcinoma cell line Caco-2Böckmann, S; Nebe, BAuthor Information 1Centre for Pharmacology and Toxicology, Institute of Experimental Pharmacology 2Clinic for Internal Medicine, Medical Faculty, University of Rostock, Schillingallee 70, 18055 Rostock, Germany Correspondence to: S. Böckmann. Fax: (+44) 0381 494 5772 E-mail: [email protected] Received 25 June 2003 Accepted 26 September 2003 European Journal of Cancer Prevention: December 2003 - Volume 12 - Issue 6 - p 469-478 Buy Abstract H-89 is a compound characterized in vitro as 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. Copyright © 2003 Wolters Kluwer Health, Inc. All rights reserved.