Interferon-α inhibits chromogranin A promoter activity in neuroendocrine pancreatic cancer cells

Abstract

Interferon-α (IFN-α) treatment can suppress the hypersecretion syndrome associated with functional neuroendocrine tumors. Chromogranin A (CgA) is a matrix protein of neuroendocrine secretory vesicles and appears to be essential for an appropriate neuroendocrine secretory function. To test the hypothesis that IFN-α can directly interfere with CgA gene transcription, we performed transient transfection studies in pancreatic neuroendocrine tumor cells employing CgA-luciferase reporter gene constructs showing that IFN-α inhibited basal and protein kinase C-dependent CgA promoter activity. Using 5′-deletion constructs in combination with mutational analysis of the proximal CgA core promoter, a cyclic AMP response element (CRE) at −71 to −64 bp was identified as the IFN-α response element of the CgA gene. Furthermore, functional studies indicated that IFN-α exerts its effect on the CgA promoter via interference with CRE binding protein (CREB)/CREB binding protein (CBP)-dependent transactivation of the CgA-CRE.