Lipid droplets (LDs) are dynamic fat storage organelles that control the use of lipids within cells. LDs play important roles in the cellular resilience against various forms of stress. However, their role in protecting cells against ferroptosis, a specific form of cell death dependent on iron and lipid peroxidation, is not yet fully understood. The aim of this master's thesis was to investigate the role of diacylglycerol acyltransferase (DGAT) enzymes, which are responsible for triglyceride synthesis and thus LD biogenesis, in the protection of cancer cells against ferroptosis. Using a breast cancer cell model, we induced ferroptosis using RSL3 and erastin and explored how combined inhibition of DGAT1 and DGAT2 affects LD formation and cell death. We found that inhibitors of DGAT enzymes decrease the level of LDs in cells and increase cell sensitivity to ferroptosis. By inhibiting individual DGAT enzymes, we determined that DGAT1 is important for cell survival under ferroptotic conditions. Using a ferroptosis inhibitor, ferrostatin-1, we confirmed that RSL3 and erastin trigger ferroptosis and discovered that ferrostatin-1 increases the amount of LDs in cells. Furthermore, we also found that docosahexaenoic acid promotes LD accumulation and increases ferroptotic cell death, while the addition of monounsaturated oleic acid is not detrimental to breast cancer cells. The findings of this master's thesis will contribute to a better understanding of the role of LDs in regulating the sensitivity of cancer cells to ferroptosis.
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