title: Targeting zebrafish and murine pituitary corticotroph tumors with a cyclin-dependent kinase (CDK) inhibitor.
abstract: Cushing disease caused by adrenocorticotropin (ACTH)-secreting pituitary adenomas leads to hypercortisolemia predisposing to diabetes, hypertension, osteoporosis, central obesity, cardiovascular morbidity, and increased mortality. There is no effective pituitary targeted pharmacotherapy for Cushing disease. Here, we generated germline transgenic zebrafish with overexpression of pituitary tumor transforming gene (PTTG/securin) targeted to the adenohypophyseal proopiomelanocortin (POMC) lineage, which recapitulated early features pathognomonic of corticotroph adenomas, including corticotroph expansion and partial glucocorticoid resistance. Adult Tg:Pomc-Pttg fish develop neoplastic coticotrophs and pituitary cyclin E up-regulation, as well as metabolic disturbances mimicking hypercortisolism caused by Cushing disease. Early development of corticotroph pathologies in Tg:Pomc-Pttg embryos facilitated drug testing in vivo. We identified a pharmacologic CDK2/cyclin E inhibitor, R-roscovitine (seliciclib; CYC202), which specifically reversed corticotroph expansion in live Tg:Pomc-Pttg embryos. We further validated that orally administered R-roscovitine suppresses ACTH and corticosterone levels, and also restrained tumor growth in a mouse model of ACTH-secreting pituitary adenomas. Molecular analyses in vitro and in vivo showed that R-roscovitine suppresses ACTH expression, induces corticotroph tumor cell senescence and cell cycle exit by up-regulating p27, p21 and p57, and downregulates cyclin E expression. The results suggest that use of selective CDK inhibitors could effectively target corticotroph tumor growth and hormone secretion.
authors.affiliation: Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Ning-Ai
authors.initials: NA
authors.lastname: Liu
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
authors.forename: Anat
authors.initials: A
authors.lastname: Ben-Shlomo
authors.forename: Kolja
authors.initials: K
authors.lastname: Wawrowsky
authors.forename: Xue-Mo
authors.initials: XM
authors.lastname: Fan
authors.forename: Shuo
authors.initials: S
authors.lastname: Lin
authors.forename: Shlomo
authors.initials: S
authors.lastname: Melmed
mesh_terms: D049913:ACTH-Secreting Pituitary Adenoma / Q000188:drug therapy*; D000324:Adrenocorticotropic Hormone; D000818:Animals; D030801:Animals, Genetically Modified; D000970:Antineoplastic Agents / Q000627:therapeutic use; D003345:Corticosterone; D019927:Cyclin E / Q000235:genetics; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D005786:Gene Expression Regulation / Q000187:drug effects; D051379:Mice; D047748:Pituitary ACTH Hypersecretion; D011687:Purines / Q000494:pharmacology* / Q000627:therapeutic use; D000077546:Roscovitine; D015027:Zebrafish / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D019927:Cyclin E; D011687:Purines; D000077546:Roscovitine; D000324:Adrenocorticotropic Hormone; D018844:Cyclin-Dependent Kinases; D003345:Corticosterone