Journal article
Enhancing Progestin Therapy with a Glucagon-Like Peptide 1 Agonist for the Conservative Management of Endometrial Cancer
Cancers, Vol.17(4), 598
02/10/2025
DOI: 10.3390/cancers17040598
PMCID: PMC11853405
PMID: 40002193
Abstract
Objective: Obesity is a major risk factor for endometrial cancer. In addition to hormone therapy with progestins, glucagon like peptide-1 receptor (GLP-1R) agonists such as semaglutide may be helpful to achieve weight loss during conservative treatment of endometrial hyperplasia or cancer. Methods: We theorized that the combination of semaglutide and the progestin levonorgestrel would be useful as a novel treatment or prevention regimen and tested this hypothesis using endometrial cancer cell lines and patient-derived organoids (PDOs). Results: Hec50, KLE, and Ishikawa endometrial cancer cells express GLP-1R, as determined by both qPCR and Western blotting, and GLP-1R agonist treatment induces GLP-1R mRNA transcription through positive feedback mechanisms in cell models. PDOs from six individuals with grade 1 endometrial carcinomas were treated with progesterone, levonorgestrel, semaglutide, or levonorgestrel + semaglutide. Multiple models demonstrated a significant reduction in viability in response to combinatorial treatment, and the effect was noted in models from both PR high- and PR low-expressing tumors. Most interesting was the induction not only of the membrane GLP-1R with treatment, but also the significant upregulation of nuclear and membrane progesterone receptors—PR and PGRMC1/2, respectively—indicating a potential positive feedback loop between semaglutide and progestins such as levonorgestrel. Conclusion: In summary, we identify synergistic molecular cross-talk between the GLP-1R and steroid hormone receptor pathways, with the potential to enhance the anticancer activity of levonorgestrel when combined with semaglutide.
Details
- Title: Subtitle
- Enhancing Progestin Therapy with a Glucagon-Like Peptide 1 Agonist for the Conservative Management of Endometrial Cancer
- Creators
- Andrea R. Hagemann - Washington University in St. LouisIan S Hagemann - Washington University in St. LouisDavid G. Mutch - Washington University in St. LouisEric J. Devor - University of IowaPaige K. Malmrose - University of Illinois Urbana-ChampaignYuping Zhang - University of IowaAbigail M. Morrison - University of IowaKristina W. Thiel - University of IowaKimberly K. Leslie - New Mexico Cancer Center
- Resource Type
- Journal article
- Publication Details
- Cancers, Vol.17(4), 598
- DOI
- 10.3390/cancers17040598
- PMID
- 40002193
- PMCID
- PMC11853405
- NLM abbreviation
- Cancers (Basel)
- ISSN
- 2072-6694
- eISSN
- 2072-6694
- Publisher
- MDPI; BASEL
- Grant note
- Department of DefenseActionable Target for the Treatment of Ovarian CancerNational Institutes of Health: P50CA265793 National Institutes of Health: the University of New Mexico Comprehensive Cancer Center: P30CA118100, K22 CA263783 National Institutes of Health: the University of Iowa Comprehensive Cancer Center: P30 CA086862
This study was supported by grants from: the Department of Defense: CDMRP/GRANT CA2220729, Progestin Therapy for Endometrial Cancer (to K.K.L. and K.W.T.); the Department of Defense: CDMRP/GRANT OC190352, Converting Mutant p53 into an Actionable Target for the Treatment of Ovarian Cancer (to K.K.L.); the Department of Defense: CDMRP/GRANT 13461923, Treating Advanced Uterine Endometrial Cancers by Reactivating p53 (to K.K.L.); the National Institutes of Health: R01 5CA99908-22 Targeted Therapy for Endometrial Cancer (to K.K.L.); the National Institutes of Health: P50CA265793, Route 66 Endometrial Cancer SPORE (to K.K.L. and D.G.M.); the National Institutes of Health: the University of New Mexico Comprehensive Cancer Center P30CA118100; the National Institutes of Health K22 CA263783 Attacking Aggressive p53 Mutants in Gynecologic Cancer (to K.W.T.); the National Institutes of Health: the University of Iowa Comprehensive Cancer Center P30 CA086862.
- Language
- English
- Date published
- 02/10/2025
- Academic Unit
- Obstetrics and Gynecology
- Record Identifier
- 9984792369002771
Metrics
5 Record Views