Induction of terminal differentiation and apoptosis in human colonic carcinoma cells by brefeldin A, a drug affecting ganglioside biosynthesis.
An appreciable increase in G(M3) with a concomitant decrease in some neolacto-series gangliosides was observed during differentiation of human colonic carcinoma HCT 116 cells induced by a differentiating agent. When the cells were treated with brefeldin A (BFA), a striking increase in de novo biosynthesis of G(M3) and a decrease in biosynthesis of neolactoseries gangliosides were observed after 6 h. Clear morphological changes to differentiated epithelial cells and an arrest of cells in the G0/G1 phase of the cell cycle were observed after 1 day of treatment. Then the cells were led to apoptosis. This activity was not affected by forskolin, which antagonizes the effects of BFA on protein transport and the Golgi apparatus. These results suggest that the differentiation-inducing activity of BFA might be due to its modulatory effect on ganglioside biosynthesis, and that a specific change in ganglioside pattern is an essential prerequisite for induction of differentiation, providing a novel target for differentiation therapy of cancer.
Faculty of Pharmaceutical Sciences, Teikyo University, Tsukui-gun, Kanagawa, Japan. nojiri-h@pharm.teikyo-u.ac.jp
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Nojiri
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Manya
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Isono
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Yamana
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Nojima
D017209:Apoptosis / Q000187:drug effects*; D020126:Brefeldin A / Q000494:pharmacology*; D002277:Carcinoma / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects*; D005576:Colforsin / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000473:pathology*; D004347:Drug Interactions; D005732:Gangliosides / Q000096:biosynthesis*; D006801:Humans; D014407:Tumor Cells, Cultured
D005732:Gangliosides; D005576:Colforsin; D020126:Brefeldin A