Functional PPAR-gamma receptor is a novel therapeutic target for ACTH-secreting pituitary adenomas.
Adrenocorticotrophic hormone (ACTH)-secreting pituitary tumors are associated with high morbidity due to excess glucocorticoid production. No suitable drug therapies are currently available, and surgical excision is not invariably curative. Here we demonstrate immunoreactive expression of the nuclear hormone receptor peroxisome proliferator-activated receptor-gamma (PPAR-gamma) exclusively in normal ACTH-secreting human anterior pituitary cells: PPAR-gamma was abundantly expressed in all of six human ACTH-secreting pituitary tumors studied. PPAR-gamma activators induced G0/G1 cell-cycle arrest and apoptosis and suppressed ACTH secretion in human and murine corticotroph tumor cells. Development of murine corticotroph tumors, generated by subcutaneous injection of ACTH-secreting AtT20 cells, was prevented in four of five mice treated with the thiazolidinedione compound rosiglitazone, and ACTH and corticosterone secretion was suppressed in all treated mice. Based on these findings, thiazolidinediones may be an effective therapy for Cushing disease
Heaney
Anthony P
AP
Department of Medicine, Cedars-Sinai Research Institute, University of California Los Angeles School of Medicine, Los Angeles, California, USA. heaneya@csmc.edu
Fernando
Manory
M
Yong
William H
WH
Melmed
Shlomo
S
D000311:Adrenal Glands / Q000503:physiopathology; D000324:Adrenocorticotropic Hormone / Q000378:metabolism*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D003480:Cushing Syndrome / Q000188:drug therapy; D005260:Female; D006801:Humans; D008024:Ligands; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000235:genetics; D009368:Neoplasm Transplantation; D010902:Pituitary Gland / Q000503:physiopathology; D010911:Pituitary Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D011333:Pro-Opiomelanocortin / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects* / Q000378:metabolism; D064249:Securin; D014157:Transcription Factors / Q000187:drug effects* / Q000378:metabolism
D008024:Ligands; D009363:Neoplasm Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D064249:Securin; D014157:Transcription Factors; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone