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Glucagon and Glucose Availability Influence Metabolic Heterogeneity and Malignancy in Pancreatic Neuroendocrine Tumour (pNET) Cells
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Resumo(s)
Cancer metabolism is a hallmark of cancer. However, the impact of systemic metabolism and diet on tumour evolution is less understood. This study delves into the role of glucagon, as a component of the pancreatic microenvironment, in regulating features of pancreatic neuroendocrine tumour (pNET) cells and the metabolic remodelling occurring in the presence and absence of glucose. pNET cell lines (BON-1 and QGP-1) and the non-malignant pancreatic α-TC1 cell line were used as models. Results showed that pNET cells responded differently to glucose deprivation than α-TC1 cells. Specifically, pNET cells upregulated the GCGR in the absence of glucose, while α-TC1 cells did so in high-glucose conditions, allowing the glucagon-related pERK1/2 activation under these conditions in pNET cells. Glucagon enhanced cancerous features in pNET BON-1 cells under glucose-deprived and hyperglucagonemia-compatible concentrations. In the α-TC1 cell line, glucagon modulated cell features under high-glucose and physiological glucagon levels. NMR exometabolome analysis revealed differences in metabolic processes based on glucose availability and glucagon stimulation across cell lines, highlighting amino acid metabolism, glycolysis, and gluconeogenesis. The expression of metabolic genes was consistent with these findings. Interestingly, QGP-1 and α-TC1 cells produced glucose in no-glucose conditions, and glucagon upregulated glucose production in α-TC1 cells. This suggests that gluconeogenesis may be beneficial for some pNET subsets, pointing out novel metabolism-based strategies to manage pNETs, as well as a step forward in endocrinology and systemic metabolism. The association between GCGR expression and malignancy and a negative correlation between glucagon receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R) expression was observed, indicating a biological role of glucagon in pNETs that deserves to be explored.
Descrição
Funding Information: The institutions are funded by Funda\u00E7\u00E3o para a Ci\u00EAncia e a Tecnologia/Minist\u00E9rio da Ci\u00EAncia, Tecnologia e Ensino Superior (FCT/MCTES, Portugal) through national funds to iNOVA4Health (UIDB/04462/2020 and UIDP/04462/2020), MOSTMICRO-ITQB (UIDB/04612/2020 and UIDP/04612/2020), and the Associated Laboratory LS4FUTURE (LA/P/0087/2020). This study was supported by a Terry Fox grant from Liga Portuguesa Contra o Cancro (TF-2022-24-DC). Cindy Mendes was funded by an FCT individual Ph.D. fellowship (2020.06956.BD). Isabel Lemos was funded by an FCT individual Ph.D. fellowship (UI/BD/154203/2022). Luis G. Gon\u00E7alves was financed by an FCT contract according to DL57/2016, [SFRH/BPD/111100/2015]. This work benefited from access to CERMAX, ITQB-NOVA, Oeiras, Portugal with equipment funded by FCT, project AAC 01/SAICT/2016. Funding Information: Metabolomics Workbench: An international repository for metabolomics data and metadata, metabolite standards, protocols, tutorials and training, and analysis tools (2016). [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26467476/ ]. This work is supported by NIH grant U2C-DK119886 and OT2-OD030544 grants. Publisher Copyright: © 2025 by the authors.
Palavras-chave
biomarkers cancer metabolism glucagon glucagon receptor (GCGR) glucagon-like peptide-1 receptor (GLP-1R) pancreatic neuroendocrine tumours (pNETs) Analytical Chemistry Chemistry (miscellaneous) Molecular Medicine Pharmaceutical Science Drug Discovery Physical and Theoretical Chemistry Organic Chemistry SDG 3 - Good Health and Well-being