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The Flavonoid Apigenin Is a Progesterone Receptor Modulator with In Vivo Activity in the Uterus
journal contributionposted on 06.05.2022, 16:46 by Matthew Dean, Julia Austin, Ren Jinhong, Michael JohnsonMichael Johnson, Daniel D Lantvit, Joanna BurdetteJoanna Burdette
Apigenin is a flavonoid with well-documented anti-cancer properties; however, its mechanisms of action are still unclear. We previously identified apigenin as a potential phytoprogestin, a natural product with a chemical scaffold that interacts with the progesterone receptor (PR). Our objective was to characterize the ability of apigenin to interact with PR through molecular docking studies, in vitro activity assays, and the ability of apigenin to elicit progestin-like effects in vivo. Molecular docking confirmed that apigenin could interact with PR, though with lower affinity than progesterone due to fewer van der Waals interactions. In Ishikawa cells stably expressing PR-B, apigenin significantly increased progesterone response element/luciferase (PRE/Luc) activity at 5 and 10 μM, but not in the parental Ishikawa cells that lack PR expression. In the presence of 100 nM of progesterone, 10 μM apigenin reduced PRE/Luc activity, indicative of mixed agonist activity. Apigenin also triggered degradation of PR in Ishikawa PR-B cells as measured by western blot. Apigenin reduced proliferation of Ishikawa cells, but through a PR-independent mechanism. In contrast, apigenin and progesterone both stimulated proliferation of T47D cells, an effect blocked by RU486. Apigenin activated other nuclear receptors evidenced by increased luciferase activity in MDA-MB-231 cells, which are PR negative. In vivo, apigenin blocked the genistein-stimulated increase in uterine epithelial cell height; stimulated endometrial expression of Hand2, a transcription factor stimulated by PR, and significantly reduced genistein-induced proliferation. In summary, apigenin is a phytoprogestin, with mixed agonist activity that demonstrates activity in vivo by hindering estrogen receptor-mediated uterine proliferation.
Research Training in Natural Product Complementary and Alternative Medicine | Funder: National Institutes of Health (National Center for Complementary and Integrative Health) | Grant ID: T32AT007533
Botanical Derived Progestins and Their Impact on Women's Health | Funder: National Institutes of Health (National Center for Complementary and Integrative Health) | Grant ID: R01AT008824
CitationDean, M., Austin, J., Jinhong, R., Johnson, M. E., Lantvit, D. D.Burdette, J. E. (2018). The Flavonoid Apigenin Is a Progesterone Receptor Modulator with In Vivo Activity in the Uterus. Discover Oncology, 9(4), 265-277. https://doi.org/10.1007/s12672-018-0333-x
PublisherSpringer Science and Business Media LLC
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Complementary and Integrative Health2.1 Biological and endogenous factors5.1 Pharmaceuticals1.1 Normal biological development and functioningCancerAnimalsApigeninCell LineCell ProliferationFemaleGene Expression RegulationHumansMolecular Docking SimulationProtein BindingRatsRats, Sprague-DawleyReceptors, ProgesteroneSignal TransductionTranscriptional ActivationUterusOncology and Carcinogenesis