Shilyansky Jonathan S, Chan Casandro J, Xiao Sophia, Gribovskaja-Rupp Irena, Quelle Dawn E, Howe James R, Dillon Joseph S, Ear Po Hien
Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA.
Department of Pharmacology and Neuroscience, University of Iowa Carver College of Medicine, Iowa City, IA.
Surgery. 2025 Mar;179:108943. doi: 10.1016/j.surg.2024.09.052. Epub 2024 Dec 10.
Semaglutide is a glucagon-like peptide 1 (GLP-1) analog that binds to GLP-1 receptors (GLP-1R) on beta-cells and neuronal cells and is used for treating type 2 diabetes and obesity. Insulin-secreting pancreatic neuroendocrine neoplasms have been reported to express high levels of GLP-1R protein, raising the possibility that GLP-1 receptor agonists could promote tumor growth. Our goal was to quantify GLP-1R expression levels in 6 neuroendocrine neoplasm cellular models and determine their proliferative response to semaglutide treatment.
Gene expression of GLP-1R in neuroendocrine neoplasm cells (BON, GOT1, NT-3, NEC913, NEC1452, and NEC1583) was measured by quantitative polymerase chain reaction. Protein expression was determined by immunofluorescent staining and Western blotting. Neuroendocrine neoplasm cells were incubated with semaglutide, and cell growth was measured using a cell viability assay. Mice harboring GOT1 xenografts were treated with semaglutide, and tumor volumes were measured.
BON, NEC1452, and NEC1583 cells expressed significantly lower levels of GLP-1R transcript and protein than GOT1, NT-3, and NEC913 cells. GOT1 and NT-3 showed the highest response to semaglutide treatment, with a 19% and 22% increase in growth. Semaglutide promotes tumor growth in mice with GOT1 xenografts by 72%.
The impact of the GLP-1 receptor agonist semaglutide on neuroendocrine cancer growth is understudied. Our data revealed that 50% of neuroendocrine neoplasm cell lines tested expressed GLP-1R, and semaglutide treatment promoted their growth. These results indicate a potential risk in the use of semaglutide in patients with neuroendocrine neoplasms expressing GLP-1R. Investigations into a larger set of neuroendocrine neoplasms would be important because they are highly heterogeneous.
司美格鲁肽是一种胰高血糖素样肽1（GLP-1）类似物，可与β细胞和神经细胞上的GLP-1受体（GLP-1R）结合，用于治疗2型糖尿病和肥胖症。据报道，分泌胰岛素的胰腺神经内分泌肿瘤表达高水平的GLP-1R蛋白，这增加了GLP-1受体激动剂可能促进肿瘤生长的可能性。我们的目标是量化6种神经内分泌肿瘤细胞模型中GLP-1R的表达水平，并确定它们对司美格鲁肽治疗的增殖反应。
通过定量聚合酶链反应测量神经内分泌肿瘤细胞（BON、GOT1、NT-3、NEC913、NEC1452和NEC1583）中GLP-1R的基因表达。通过免疫荧光染色和蛋白质印迹法测定蛋白质表达。将神经内分泌肿瘤细胞与司美格鲁肽一起孵育，并使用细胞活力测定法测量细胞生长。用司美格鲁肽治疗携带GOT1异种移植物的小鼠，并测量肿瘤体积。
与GOT1、NT-3和NEC913细胞相比，BON、NEC1452和NEC1583细胞表达的GLP-1R转录本和蛋白质水平显著较低。GOT1和NT-3对司美格鲁肽治疗的反应最高，生长分别增加了19%和22%。司美格鲁肽使携带GOT1异种移植物的小鼠的肿瘤生长增加了72%。
GLP-1受体激动剂司美格鲁肽对神经内分泌癌生长的影响研究不足。我们的数据显示，所测试的神经内分泌肿瘤细胞系中有50%表达GLP-1R，司美格鲁肽治疗促进了它们的生长。这些结果表明，在表达GLP-1R的神经内分泌肿瘤患者中使用司美格鲁肽存在潜在风险。对更多神经内分泌肿瘤进行研究很重要，因为它们具有高度异质性。
