Up-regulation of cyclooxygenase-1 in neuroblastoma cell lines by retinoic acid and corticosteroids

Abstract

Cyclooxygenases-1 and -2 are both expressed in neuronal cells in vivo. In the neuroblastoma cell lines NG108 and N2a, however, only cyclooxygenase-1 was detectable. Differentiation of the cells with retinoic acid increased cyclooxygenase-1 mRNA and protein expression within 24 and 48 h, respectively. A further increase was observed when the cells were concomitantly treated with the glucocorticoid dexamethasone (a 2-3-fold increase compared with retinoic acid alone). In the absence of retinoic acid, dexamethasone only slightly up-regulated cyclooxygenase-1 expression. The inhibitor of protein synthesis cycloheximide abrogated the effect of dexamethasone, indicating the involvement of newly synthesised proteins. Retinoic acid increased the transcription of cyclooxygenase-1 mRNA, determined with a luciferase-coupled promoter construct. Dexamethasone only slightly augmented cyclooxygenase-1-promoter activity but increased cyclooxygenase-1 mRNA stability. Other corticosteroids, hydrocortisone and aldosterone, also up-regulated cyclooxygenase-1 whereas neurosteroids or oestrogen were ineffective. Up-regulation was mediated primarily by the glucocorticoid receptor, because the receptor antagonist RU486 strongly reduced the effects of all corticosteroids. This indicated that in NG108 cells, the mineralocorticoid aldosterone may bind to the glucocorticoid receptor. Treatment of NG108 or N2a cells with corticosteroids did not alter the morphological phenotype obtained during differentiation. We thus show that corticosteroids, which down-regulate cyclooxygenase expression in most cell types, up-regulate cyclooxygenase-1 during neuronal differentiation.