Interferon-gamma inhibits cellular proliferation and ACTH production in corticotroph tumor cells through a novel janus kinases-signal transducer and activator of transcription 1/nuclear factor-kappa B inhibitory signaling pathway.
Interferon-gamma (IFNG) is a cytokine that exerts potent antiproliferative and tumoricidal effects in a variety of cancers. Moreover, IFNG modulates normal pituitary hormone secretion, and was shown to inhibit the expression of the ACTH precursor POMC in murine ACTH-secreting AtT-2010/21/2008 tumor cells. We have studied the functional role of IFNG on pituitary tumor cells, focusing on the involvement of IFNG in the molecular events leading to the control of POMC transcriptional repression. Herein, it is shown that IFNG inhibits AtT-20 tumor cell proliferation without inducing apoptosis. Unexpectedly, an activated janus kinases-signal transducer and activator of transcription (JAK-STAT1) cascade is required for IFNG inhibitory action on POMC promoter activity. Factor-kappa B (NF-kappaB) is necessary for the inhibitory action of IFNG on Pomc transcription, since loss of NF-kappaB activity with IkappaB super-repressor abolishes this effect. In addition, 1 and 2 IFNG receptor immunoreactivity was detected in human corticotropinoma cells. Interestingly, IFNG inhibits ACTH production from these cells in primary cell culture, without affecting basal ACTH biosynthesis in normal non-tumoral pituitary cells. In conclusion, our data show for the first time that POMC transcription can be negatively regulated by a JAK-STAT1 and NF-kappaB-dependent pathway.
Labeur
Marta
M
Department of Neuroendocrinology, Department of Molecular Neurogenetics Department of Inflammatory Disorders of the CNS at the Max Planck Institute of Psychiatry, Munich 80804, Germany. labeur@mpipsykl.mpg.de
Refojo
Damian
D
Wölfel
Barbara
B
Stalla
Johanna
J
Vargas
Vivian
V
Theodoropoulou
Marily
M
Buchfelder
Michael
M
Paez-Pereda
Marcelo
M
Arzt
Eduardo
E
Stalla
Günter K
GK
D000324:Adrenocorticotropic Hormone / Q000096:biosynthesis*; D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D053612:Janus Kinases / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D010911:Pituitary Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects
D016328:NF-kappa B; D050794:STAT1 Transcription Factor; D011333:Pro-Opiomelanocortin; D007371:Interferon-gamma; D000324:Adrenocorticotropic Hormone; D053612:Janus Kinases