Suppression of glucocorticoid-induced elevation of alkaline phosphatase in C-4-1 cells by inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and reversal of the suppression by mevalonate.
Cell line C-4-1 which produces alkaline phosphatase (EC 3.1.1.4) of the placental type in response to glucocorticoids was grown in the presence of inhibitors of mevalonate formation for periods ranging from 1 to 4 days. When C-4-1 cells were incubated in the presence of 25-hydroxycholesterol (1 microM) or compactin (11.6 microM) the induction of alkaline phosphatase by 0.2 microM dexamethasone was suppressed. This suppression could be partially prevented by the addition of mevalonolactone to the growing culture. The reversal effect by mevalonate was most evident with compactin, a well known competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. In contrast, the effect of tunicamycin which inhibits N-linked protein glycosylation and also prevents alkaline phosphatase induction by glucocorticoids could not be reversed by mevalonate. These results implicate mevalonate in alkaline phosphatase induction, possibly through its role as a precursor of dolichols.
D000469:Alkaline Phosphatase / Q000378:metabolism*; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D005944:Glucosamine / Q000378:metabolism; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008798:Mevalonic Acid / Q000096:biosynthesis / Q000494:pharmacology*; D002583:Uterine Cervical Neoplasms
D005938:Glucocorticoids; D006888:Hydroxycholesterols; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C007997:25-hydroxycholesterol; D003907:Dexamethasone; D000469:Alkaline Phosphatase; D005944:Glucosamine; D008798:Mevalonic Acid