Effect of epidermal growth factor and prostaglandin on the expression of aromatase (CYP19) in human adrenocortical carcinoma cell line NCI-H295R cells.

We investigated the effects of epidermal growth factor (EGF) and prostaglandins (PG) on the expression of aromatase (CYP19) in human adrenocortical carcinoma cell line NCI-H295R cells. EGF significantly increased aromatase activity and CYP19 gene transcript in NCI-H295R cells. Exon PII was selected from among several tissue-specific exon I regions. Promoter II that abuts on exon PII was activated by EGF. PGE(2) also significantly increased aromatase activity, CYP19 gene transcript, and promoter II activity. The results of experiments using protein kinase (PK) inhibitors suggest that the cAMP-PKA signaling pathway is involved in the up-regulation of aromatase expression by EGF. PGE(2) activated promoter II activity in 4 h, while 12 h was required for its activation by EGF. In addition, PGE(2) was secreted from NCI-H295R cells in response to EGF. Selective agonists for prostaglandin receptors EP(1) and EP(2) significantly increased aromatase activity, which was decreased by the corresponding antagonists. Finally, antagonists for EP(1) and EP(2) inhibited the up-regulation of aromatase expression following EGF. These results suggest that PGE(2) secondarily acts as an autocrine signal in the up-regulation of aromatase expression by EGF in NCI-H295R cells.