title: Activation of protein kinase C augments butyrate-induced differentiation and turnover in human colonic epithelial cells in vitro.
abstract: As the colonic epithelium is physiologically exposed to butyrate and to activators of protein kinase C, we examined the effect of the protein kinase C signalling pathway on butyrate-induced expression of markers of differentiation. Activators and inhibitors of protein kinase C were used in combination with butyrate and effects on the expression of markers of differentiation examined in colon cancer cell lines. When the protein kinase C activator phorbol myristate acetate (100 nM) was added for 24 h prior to the addition of 2 mM butyrate, there was a synergistic increase in alkaline phosphatase activity (154 +/- 11% above that for butyrate alone, P = 0.003) in a concentration- and time-dependent manner. Butyrate-induced expression of carcinoembryonic antigen and interleukin-8, dome formation and cell turnover were also markedly augmented by pre-treatment with phorbol myristate acetate. A similar effect was observed with propionate or acetate (but not other differentiating agents), when phorbol myristate acetate and butyrate were added concurrently, or when other protein kinase C activators were used. Pharmacological inhibition of protein kinase C activity did not alter butyrate-induced alkaline phosphatase activity, but abrogated the augmentation induced by phorbol myristate acetate. We conclude that protein kinase C does not mediate the differentiating effects of butyrate on colon cancer cells, but its activation regulates butyrate-induced cellular differentiation.
authors.affiliation: University of Melbourne Department of Medicine, Royal Melbourne Hospital, University of Melbourne Department of Surgery, Western Hospital, Melbourne, Victoria, Australia.
authors.forename: K L
authors.initials: KL
authors.lastname: Rickard
authors.forename: P R
authors.initials: PR
authors.lastname: Gibson
authors.forename: G P
authors.initials: GP
authors.lastname: Young
authors.forename: W A
authors.initials: WA
authors.lastname: Phillips
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002087:Butyrates / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D004261:DNA Replication / Q000187:drug effects; D004789:Enzyme Activation; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D002087:Butyrates; D016209:Interleukin-8; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate