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.
目的：肥胖是子宫内膜癌的主要风险因素。除孕激素激素治疗外，胰高血糖素样肽-1受体（GLP-1R）激动剂（如司美格鲁肽）可能有助于在子宫内膜增生或癌症的保守治疗期间实现减重。方法：我们提出假设，认为司美格鲁肽与孕激素左炔诺孕酮的联合应用可作为新型治疗或预防方案，并通过子宫内膜癌细胞系和患者来源类器官（PDOs）验证该假说。结果：通过qPCR和Western blotting检测发现，Hec50、KLE和Ishikawa子宫内膜癌细胞均表达GLP-1R，且GLP-1R激动剂处理通过正反馈机制诱导细胞模型中GLP-1R mRNA的转录。对六例1级子宫内膜癌患者的PDOs分别进行孕酮、左炔诺孕酮、司美格鲁肽或左炔诺孕酮+司美格鲁肽处理。多个模型显示联合治疗能显著降低细胞活力，且在PR高表达和PR低表达的肿瘤模型中均观察到该效应。最值得注意的是，治疗不仅诱导了膜GLP-1R的表达，还显著上调了核孕激素受体PR及膜孕激素受体PGRMC1/2，表明司美格鲁肽与左炔诺孕酮等孕激素之间可能存在正反馈环路。结论：本研究揭示了GLP-1R与类固醇激素受体通路之间存在协同分子互作机制，当左炔诺孕酮与司美格鲁肽联用时，可能增强其抗癌活性。
肿瘤(癌症)患者之家