Unravelling the role of fatty acid metabolism in the sensitivity to punicic acid-induced ferroptosis

Details

Supervisors

Larondelle, Yvan ; Vermonden, Perrine

Faculty

Faculté des bioingénieurs

Degree label

Master [120] : bioingénieur en sciences agronomiques, à finalité spécialisée

Abstract

Cancer is an ongoing battle, and despite significant progress made in understanding the disease and developing treatments, cancer remains one of the leading causes of mortality worldwide. Prostate cancer ranks as the second most common cancer in men and is lacking a definitive cure. In recent years, there has been a growing focus on the metabolic rewiring of cancer cells, offering new avenues for therapeutic interventions. One intriguing aspect is the influence of dietary choices on cancer development. It is well established that cancer cells, and particularly prostate cancer cells, heavily rely on fatty acids for various essential processes, including membrane synthesis, energy production and signalling pathways. Peroxidisable fatty acids, including long-chain polyunsaturated fatty acids (PUFAs) and conjugated linolenic acids (CLnAs), have been shown to exhibit cytotoxic effects on cancer cells. The cytotoxicity is thought to be induced by ferroptosis, a recently described form of cell death. Ferroptosis is characterised by the accumulation of lipid hydroperoxides, generated through the peroxidation of PUFA. However, the precise mechanism underlying PUFA-induced cytotoxicity remains poorly understood. Differences in cancer model responses to PUFAs treatments have been observed, suggesting variations in the metabolism of these fatty acids within the cells. This master's thesis aims to investigate fatty acid metabolism in the PC3 and 22RV1 prostate cancer cell lines to unravel the potential link between their divergent sensitivity to highly peroxidisable PUFAs and differences in fatty acid metabolism. The first part of this work has focused on the metabolism of ω3 and ω6 PUFAs and reveals both similarities and distinct behavioural patterns in the two cell lines. Interestingly, PC3 cells, which are more sensitive to peroxidisable PUFAs, exhibit a higher enrichment and storage of these PUFAs in lipid droplets, while 22RV1 cells demonstrate lower activity in ω3 and ω6 PUFA transformation, with a higher propensity for membrane storage. The insertion of peroxidisable PUFAs into phospholipids is a critical factor in sensitising cells to ferroptosis, suggesting the presence of more robust protective mechanisms in 22RV1 cells. The second part of this work has focused on the metabolism of punicic acid (PunA), a CLnA that holds particular interest due to its high abundance in pomegranate seed oil. The results do not suggest significant differences in the fate of PunA between the two cell lines. However, an intriguing finding emerges as PunA appears to undergo a cycle of β-oxidation in the cells, which has never been reported in the literature before. This discovery suggests that β-oxidation could impede the accumulation and toxicity of PunA, presenting a potential obstacle to its effectiveness. Overall, this master's thesis provides valuable insights into the behaviour of prostate cancer cell lines when exposed to peroxidisable PUFAs, shedding light on potential mechanisms underlying their differential sensitivity. These findings contribute to our understanding of prostate cancer metabolism and offer potential avenues for further research and therapeutic interventions.