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Metabolic kinetics upon the exposure to glucagon in hepatocellular carcinoma (HCC)
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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.
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Palavras-chave
Metabolic Kinetics Lucagon in Hepatocellular Carcinoma