Publicação
Metabolic kinetics upon the exposure to glucagon in hepatocellular carcinoma (HCC)
| datacite.subject.fos | Ciências Médicas | pt_PT |
| dc.contributor.advisor | Gonçalves, Luís Gafeira | |
| dc.contributor.advisor | Serpa, Jacinta | |
| dc.contributor.author | Costa, Edward Rylatt | |
| dc.date.accessioned | 2024-12-23T11:10:25Z | |
| dc.date.available | 2025-12-20T01:30:39Z | |
| dc.date.issued | 2024-11-20 | |
| dc.description.abstract | Cancer metabolism research has advanced significantly over the past two decades yet the impact of systemic metabolism and diet on cancer remains underexplored. Systemic metabolic regulators, such as insulin and glucagon, can influence cancer cells by triggering metabolic adaptations crucial for tumour survival within the tumour and organ microenvironment (TOME). While insulin's role in cancer models is well-studied, the effects of glucagon and hyperglucagonemia (>100 pmol/mL) on TOME and cancer metabolism are less understood. This work hypothesizes that glucagon plays a key role in hepatocellular carcinoma (HCC) metabolism due to the liver's role in glucagon clearance, leading to a glucagon-rich hepatic environment. This thesis aims to explore glucagon's impact on metabolic remodelling in HCC, focusing on cancer cell survival and tumour growth. To achieve this goal, we planned to use 1H-NMR metabolomics to visualise the influence of glucagon exposure at 0, 50, and 250 pg/mol on the exometabolome of two HCC cell lines, HepG2 and SNU449, over 0 h, 24 h, and 48 h in the presence and absence of glucose. The findings revealed that hyperglucagonemia, characterised by elevated glucagon levels, drives significant amino acid catabolism in HepG2 cells, particularly under glucose-deprived conditions. The study demonstrates that glucagon increases the consumption of gluconeogenic amino acids, such as histidine, methionine, and branched-chain amino acids (BCAAs), promoting gluconeogenesis and allowing HepG2 cells to maintain survival in nutrient-stressed environments. This metabolic flexibility enables HepG2 cells to adapt by utilizing alternative energy sources like amino acids and lactate, supporting cell growth even when glucose is scarce. In contrast, SNU449 cells showed lower metabolic adaptability, exhibiting diminished cell growth under glucose-free conditions and a reduced response to glucagoninduced metabolic changes. This highlights the differential metabolic characteristics of the two HCC cell lines. Furthermore, the study explored glucagon's effect on the chemoresistance of HCC cells to cisplatin. The results suggest that glucagon had little impact on the exometabolome of HepG2 cells exposed to cisplatin, likely due to the putative dominant effect of cisplatin-induced metabolism disruption upon DNA damage. The suppression of glucagon's typical metabolic pathways in the presence of cisplatin indicates that glucagon's role may be limited under conditions of severe cellular stress. However, in SNU449 cells, glucagon reduced amino acid consumption in glucose-free conditions, suggesting a protective mechanism that allows these cells to downregulate energy-intensive processes and conserve metabolic resources under cisplatin-induced stress. One of the key observations is that glucagon's metabolic effects were not significant in either cell line when glucose was abundant. In glucose-rich environments, cells primarily rely on glycolysis for energy production, overshadowing glucagon's role in promoting gluconeogenesis and amino acid catabolism. However, under glucose-deprived conditions, glucagon's influence on metabolism becomes more pronounced, especially in HepG2 cells, which exhibited increased reliance on amino acids and other carbon sources for energy production. In summary, this thesis underscores glucagon's role in driving amino acid catabolism and metabolic reprogramming in HCC cells, particularly under glucose-deprived conditions. The differential responses of HepG2 and SNU449 cells to glucagon and cisplatin highlight the complex interplay between cancer cell phenotype, metabolism and chemoresistance in HCC, with potential implications for therapeutic strategies targeting metabolic pathways in different stages of cancer treatment. | pt_PT |
| dc.identifier.tid | 203772008 | pt_PT |
| dc.identifier.uri | http://hdl.handle.net/10362/176660 | |
| dc.language.iso | eng | pt_PT |
| dc.subject | Metabolic Kinetics | pt_PT |
| dc.subject | Lucagon in Hepatocellular Carcinoma | pt_PT |
| dc.title | Metabolic kinetics upon the exposure to glucagon in hepatocellular carcinoma (HCC) | pt_PT |
| dc.type | master thesis | |
| dspace.entity.type | Publication | |
| rcaap.rights | openAccess | pt_PT |
| rcaap.type | masterThesis | pt_PT |
| thesis.degree.name | Investigação Biomédica | pt_PT |