Unraveling the differential cytotoxicity of conjugated linolenic acids using breast cancer cell lines as models

Details

Supervisors

Larondelle, Yvan ; Rezsohazy, René

Faculty

Faculté des bioingénieurs

Degree label

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

Abstract

With nearly 10 million of deaths in 2020, cancer is one of the leading causes of death globally. Among them, breast cancer is the fifth deadliest cancer, the first among women. Cancers are diseases characterized by the transformation of cells into abnormal cells resulting in uncontrolled cell proliferation leading to the formation of tumors. Each cancer type has its own characteristics, including its response to treatment, which means that they are not suitable for all cancers. Breast cancers can be classified depending on their receptor status. Triple-negative breast cancer (TNBC), the most aggressive subtype of breast cancer, still lacks a targeted therapy capable of addressing its molecular characteristics. Interestingly, several cell lines representing this subtype have been shown to be sensitive to ferroptosis. This recently discovered cell death is characterized by the accumulation of lipid hydroperoxides in the cell membrane and can be triggered by the supplementation with conjugated linolenic acids (CLnAs), present in some seed oils. However, the mechanisms underlying CLnA-induced ferroptotic cell death remain unclear. The cytotoxicities of five natural CLnA isomers, namely punicic acid 􏰴P􏰵nA􏰶􏰷 􏰸-eleostearic acid 􏰴􏰸-ESA􏰶􏰷 􏰹-eleostearic acid 􏰴􏰹-ESA), catalpic acid (CA) and jacaric acid (JA), were assessed on two cell lines belonging to distinct breast cancer subtypes, Hs578T cells (from the TNBC subtype) and MCF7 cells (from the Luminal A subtype). Cell viability assays confirmed the higher sensitivity of Hs578T cells to CLnAs compared to MCF7 cells with jacaric acid being systematically the most cytotoxic isomer regardless of the cell line. The impact of CLnAs was also tested on three- dimensional spheroids, a more complex and representative tumor model, which exhibited a stronger resistance to CLnAs but still revealed a higher sensitivity for the Hs578T cell line. Fatty acid profiles were performed on both cell lines to elucidate the underlying causes of the differences in sensitivity between Hs578T and MCF7 cells and in cytotoxicity between CLnAs. The sensitivity of cancer cells does not seem to be due to a higher absorption of CLnAs. However, the rate of uptake of the different isomers seems to reflect their cytotoxic potential. Only a limited proportion of CLnAs is converted to CLAs in both cell lines, supporting the existence of additional pathways of CLnA metabolic processing and/or degradation. The lipid peroxidation rate was also assessed in the two cell lines. This key hallmark of ferroptosis was found to be proportional to the cell sensitivity and the cytotoxic potential of CLnAs. By unraveling the differential cytotoxicity of CLnAs using breast cancer cell lines as a model, this master's thesis puts forward the complexity of mechanisms underlying cellular responses to CLnA isomer supplementation. This study raises questions and highlights aspects that confirm that CLnA supplementation could become a therapeutic window to induce ferroptosis in cancer cells, and more particularly in TNBC cells.

Citations

• APA

Mikolajczak, R. (2022). Unraveling the differential cytotoxicity of conjugated linolenic acids using breast cancer cell lines as models.