GLP-1R agonist promotes proliferation of neuroendocrine neoplasm cells expressing GLP-1 receptors

Abstract

Objectives: 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.

Methods: 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.

Results: 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%.

Conclusion: 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.