title: Isoliquiritigenin exhibits anti-proliferative properties in the pituitary independent of estrogen receptor function.
abstract: The plant flavonoid isoliquiritigenin (ISL) is a botanical estrogen widely taken as an herbal supplement to ease the symptoms of menopause. ISL has been also shown to have anti-tumor properties in a number of cancer cell backgrounds. However, the effects of ISL on normal cells are less well known and virtually unstudied in the context of the pituitary gland. We have established a pituitary explant culture model to screen chemical agents for gene expression changes within the pituitary gland during a period of active proliferation and differentiation. Using this whole-organ culture system we found ISL to be weakly estrogenic based on its ability to induce Cckar mRNA expression, an estrogen receptor (ER) mediated gene. Using a range of ISL from 200nM to 200μM, we discovered that ISL promoted cell proliferation at a low concentration, yet potently inhibited proliferation at the highest concentration. ICI 182,780 failed to antagonize ISL's repression of pituitary cell proliferation, indicating the effect is independent of ER signaling. Coincident with a decrease in proliferating cells, we observed down-regulation of transcript for cyclin D2 and E2 and a strong induction of mRNA and protein for the cyclin dependent kinase inhibitor Cdkn1a (p21). Importantly, high dose ISL did not alter the balance of progenitor vs. differentiated cell types within the pituitary explants and they seemed otherwise healthy; however, TUNEL staining revealed an increase in apoptotic cell death in ISL treated cultures. Our results merit further examination of ISL as an anti-tumor agent in the pituitary gland.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, 524 Burrill Hall, 407 South Goodwin Avenue, Urbana, IL 61801, United States.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Weis
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, 524 Burrill Hall, 407 South Goodwin Avenue, Urbana, IL 61801, United States. Electronic address: raetzman@life.illinois.edu.
authors.forename: Lori T
authors.initials: LT
authors.lastname: Raetzman
mesh_terms: D019070:Cell Lineage; D049109:Cell Proliferation / Q000187:drug effects*; D047188:Chalcones / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D010902:Pituitary Gland / Q000166:cytology / Q000187:drug effects*; D011960:Receptors, Estrogen / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D047188:Chalcones; D011960:Receptors, Estrogen; C040920:isoliquiritigenin
keywords: Estrogen; Isoliquiritigenin; Pituitary development; Proliferation