The somatostatin analogue octreotide inhibits POMC transcription by a mechanism involving Nurr77 and STAT3

Abstract

Somatostatin analogues are known to decrease ACTH secretion, but their action on POMC transcription is still obscure. Treatment of the AtT20 corticotrophinoma cells with octreotide reduced POMC transcription in a pertussis toxin sensitive manner. Octreotide inhibited Nur transcriptional activity and decreased Nur77 mRNA levels. Furthermore it had no effect on the POMC promoter bearing a mutation in the Nur response element indicating that its inhibitory action is through this site. On this site, Nur77 interacts with STAT1–3 to increase POMC transcription. Indeed, octreotide decreased STAT3 phosphorylation, although it had no effect on the total STAT3 levels. In addition it inhibited CRE transcriptional activity and CREB phosphorylation at Ser133. Although CREB does not bind directly to the POMC promoter, it was found to interact with and increase the stability of Nur77-STAT3 binding. These data show that octreotide by inhibiting each component of the Nur-STAT-CREB complex decreases POMC transcription and subsequently ACTH secretion, confirming the inhibitory effect of octreotide on ACTH at transcriptional level in pituitary tumor cells.