Efecte modulador de la leptina i polifenols en la funció mitocondrial i metabolisme de la cèl·lula tumoral

Abstract

Cancer cells exhibit differential characteristics such as maintenance of proliferative signals, evasion of tumor suppressor response, resistance to apoptosis and metabolic reprogramming to sustain a high proliferation. First studies regarding metabolism of tumor cells suggested that, due to mitochondrial dysfunction of these cells, the oxidation of glucose to lactate was the main energy pathway for tumor survival. However, in the recent years it has been found that cancer cells require the presence of functional mitochondria, thus acquiring this organelle a greater importance in cancer metabolism. Leptin, a hormone secreted by adipose tissue, has been considered the link between obesity and the increased risk of breast cancer in postmenopausal women. In this thesis we aimed to study the effects of leptin in breast cancer at the metabolic level. Moreover, polyphenols are compounds consumed through diet that act as antioxidants at low doses, preventing the appearance of cancerous conditions, while at high doses play a prooxidant role. In this regard, another objective of this thesis was to study the effects of the polyphenols xanthohumol (XN), 8-prenylnaringenin (8-PN) and resveratrol (RSV) on the metabolism of breast and colon cancer. To achieve these objectives it was studied: i) the effects of leptin on mitochondrial dynamics and functionality and energy metabolism in MCF-7 breast cancer line; ii) the influence of the polyphenols XN and 8-PN on oxidative stress and mitochondrial functionality in MCF-7 cell line; and iii) the effects of RSV on mitochondrial functionality and energy metabolism in SW620 colon cancer line. The results indicate that leptin promotes mitochondrial functionality in MCF-7 breast cancer cells by improving quality control. This hormone also increases the oxidation of fatty acids to keep the energy production, while glucose is preferably allocated to biosynthetic pathways. Thus, leptin induces a metabolic reprogramming which makes it possible a better utilization of metabolic substrates and a reduced oxidative stress, conferring advantages for cell survival. Moreover, XN and 8-PN are able to modulate oxidative stress of MCF-7 cell line through regulation of mitochondrial functionality. Finally, it was found that RSV stimulates mitochondrial biogenesis and metabolism, favouring fatty acid oxidation as main energy source, in SW620 colon cancer cells and this state of increased lipid oxidation leads to a high oxidative stress which results in apoptosis. In conclusion, the results of this thesis contribute to explain the promoter effect of leptin in breast cancer and the protective effect of some polyphenols in breast and colon cancer. Furthermore, they also suggest the reprogramming of tumor metabolism as an interesting strategy to increase the effectiveness of antitumor therapies.