{"doi":"10.3390/cancers17040598","title":"Enhancing Progestin Therapy with a Glucagon-Like Peptide 1 Agonist for the Conservative Management of Endometrial Cancer","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.","journal":"Cancers","year":2025,"id":511715,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9551,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":231283,"name":"Ian S. Hagemann","orcid":"0000-0002-3855-9745","position":1,"is_corresponding":false},{"id":1723,"name":"David G. Mutch","orcid":"0000-0002-6921-1581","position":2,"is_corresponding":false},{"id":461443,"name":"Eric J. Devor","orcid":"0000-0001-7131-8604","position":3,"is_corresponding":false},{"id":879378,"name":"Paige K. Malmrose","orcid":null,"position":4,"is_corresponding":false},{"id":76227,"name":"Yuping Zhang","orcid":"0000-0001-8986-0354","position":5,"is_corresponding":false},{"id":1057430,"name":"Abigail M. Morrison","orcid":"0000-0001-6935-5246","position":6,"is_corresponding":false},{"id":461445,"name":"Kristina W. Thiel","orcid":"0000-0001-8295-864X","position":7,"is_corresponding":false},{"id":461446,"name":"Kimberly K. Leslie","orcid":"0000-0002-2704-8990","position":8,"is_corresponding":false},{"id":581717,"name":"Andrea R. Hagemann","orcid":"0000-0002-3484-0046","position":0,"is_corresponding":true}],"reference_count":36,"raw_metadata":null,"created_at":"2026-07-19T02:48:01.269605Z","pmid":"40002193","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}