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¹ Departments of Pathology and
² Virology, Haartman Institute, University of Helsinki, Helsinki, Finland
³ Department of Pediatrics, Kuopio University and University Hospital, Kuopio, Finland

(Requests for offprints should be addressed to J Liu, Department of Pathology, Haartman Institute, P.O. Box 21, University of Helsinki, FIN-00014 Helsinki, Finland; Email: Jiangi.Liu{at}helsinki.fi)

(J Liu and X-D Li contributed equally to this work)

Adrenocorticotropin is the major regulator of adrenocortical development and function. It acts mainly through the cAMP-dependent protein kinase A (PKA) pathway. Our aim was to study the interaction of tumor necrosis factor- (TNF) and the PKA pathway in adrenocortical cell proliferation and apoptosis. The PKA activator Dibutyryl cAMP ((Bu)₂cAMP) strongly induced differentiation and inhibited proliferation in the human adrenocortical cell line NCI-H295R (H295R). TNF induced apoptosis of H295R cells. Interestingly, (Bu)₂cAMP treatment clearly enhanced TNF-induced apoptosis in H295R cells, but not in another human adrenocortical cell line SW-13, the mouse adrenocortical Y-1 cell line or the human HeLa cell line. This synergistic effect was not due to the (Bu)₂cAMP-induced glucocorticoid secretion since dexamethasone had no significant effect on the TNF-induced apoptosis. (Bu)₂cAMP treatment rapidly increased the expression of the proto-oncogene c-myc in H295R cells, but not in SW-13, Y-1 or HeLa cells. In transient c-myc transfection assay, c-myc expression associated with decreased expression of the proliferation marker Ki-67 in H295R cells. In conclusion, cAMP-dependent protein kinase activation reduced proliferation and augmented TNF-induced apoptosis in adrenocortical H295R cells, and these effects were associated with increased c-myc expression.

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