Interferon-γ inhibits cellular proliferation and ACTH production in corticotroph tumor cells through a novel JAK-STAT1/NF-κB inhibitory signalling pathway

Cushing's disease is a severe clinical condition caused by hypersecretion of corticosteroids due to excessive ACTH secretion from a pituitary adenoma. In the last years there was only few progress elucidating the molecular mechanisms responsible for constitutive and autonomous ACTH secretion of pituitary corticotrophinomas. As a consequence, no effective drug therapy is currently available, particularly if surgical excision is not successful. IFN-γ is a cytokine that exerts potent antiproliferative and tumoricidal effects in a variety of cancers. Moreover, IFN-γ modulates normal pituitary hormone secretion, and has been shown to inhibit the expression of the precursor of ACTH, POMC, in murine ACTH secreting AtT-20 tumor cells. In order to identify molecular targets for the treatment of Cushing's disease we have studied the involvement of IFN-γ in the molecular events leading to the control of POMC transcriptional repression. We demonstrate that IFN-γ inhibits proliferation and POMC transcriptional activity of AtT-20 tumor cells via the activation of the JAK-STAT1 signalling cascade. Furthermore, the transcription factor NF-κB is associated with the transcriptional inhibition of POMC by IFN-γ. In addition, α and β IFN-γ receptor subunits are present at the protein level in human corticotroph tumor cells. Interestingly, IFN-γ inhibits ACTH production from human ACTH secreting tumor cells in primary cell culture without affecting basal ACTH biosynthesis in normal non-tumoral pituitary cells. In conclusion, our data for the first time show that POMC transcription can be negatively regulated by a JAK-STAT1 and NF-κB-dependent signalling pathway. The development of therapeutic agents that target this novel IFN-γ-JAK-STAT1/NF-κB pathway could therefore prove valuable for the effective treatment of Cushing's disease.