The relationship between the expression of Pituitary Adenylate Cyclase-Activating Polypeptide & its receptors and apoptosis in human pituitary adenomas

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Pituitary adenylate cyclase-activating polypeptide (PACAP) was originally isolated from hypothalamic tissue based on its ability to stimulate cAMP production in cultured anterior pituitary cells. Recent studies have suggested a functional role for PACAP in the apoptosis of brain cells. However, the role of PACAP in regulating apoptosis in human pituitary adenomas has not previously been examined. Analysis of the cultured human pituitary adenoma cell line HP75 and human pituitary adenomas, which expresses all three major PACAP receptors, showed that both PACAP-38 and PACAP-27 inhibited TGF-s1-induced apoptosis. Treatment with the PACAP receptor antagonists PACAP 6?38 (PACAP type I receptor antagonist) and (p-chloro-D-Phe6, Leu17)-VIP (PACAP type II receptor antagonist) blocked the effects of PACAP-38 on the inhibition of transforming growth factor-s1 (TGF-s1)-induced apoptosis, confirming the specificity of the role of PACAP. Immunocytochemical analysis of the cell cycle cyclin-dependent kinase inhibitor p16, p21, p27 showed only p27 expression in human pituitary adenomas. These results indicate that PACAP is a highly specific inhibitor of TGF-s1-induced apoptosis in the HP75 human pituitary adenoma cell line. Pituitary adenomas expressed p16, p21, p27 and p53 mRNAs by real time RT-PCR. However, in protein level, only p27 expressed in human pituitary adenomas. Moreover, cyclin D3 as oncogene highly expressed in human pituitary adenomas but not cyclin B1 or D1.