REPOSITORY > RESULTS

Abstract

Lipid droplets (LDs) are intracellular organelles that store lipids, mainly triacylglycerols (TAGs) and sterol esters. LDs were initially considered just inert fat reservoirs but have now been identified as critical players in the cellular stress response, especially in cancer cells. In response to various kinds of stress, including nutrient deprivation or excess, LD formation is induced. Recent studies have indicated that there is a complex association between LDs and autophagy. The primary goal of this dissertation was to investigate the crosstalk between autophagy and LD metabolism in promoting cancer cell survival under nutrient stress conditions. Our findings demonstrate that LDs are dynamically formed and broken down in HeLa cervical cancer cells depending on the severity and duration of nutrient stress. Notably, LD biogenesis was upregulated within hours of amino acid starvation, whereas milder starvation in the absence of serum predominantly stimulated LD breakdown pathways. However, during prolonged serum starvation there was a gradual but significant LD accumulation. Inhibition of diacylglycerol acyltransferase (DGAT) 1 and 2 enzymes, which are essential for TAG synthesis and LD formation, decreased the levels of LDs in cells exposed to both conditions of nutrient stress. Autophagy contributed to LD biogenesis during acute starvation, but not during cell growth in nutrient-rich conditions and during serum starvation, when selective autophagic breakdown of LDs through lipophagy was observed. Finally, we demonstrate that joint inhibition of autophagy and DGAT-mediated LD biogenesis, rather than combined suppression of autophagy and lipolysis, is an efficient way to compromise cancer cell survival during both amino acid and serum starvation conditions. In conclusion, the results from this dissertation suggest that autophagy and LDs cooperate in the protection of HeLa cervical cancer cells against nutrient deficiency-induced stress. Our findings provide a better understanding of the interplay between autophagy and LDs in cancer cell survival and could have important implications for the development of novel cancer therapies.