Effect of different fatty acids combined with punicic acid on prostate cancer cells

Details

Supervisors

Larondelle, Yvan

Faculty

Faculté des bioingénieurs

Degree label

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

Abstract

Cancer is the second leading cause of death worldwide with 10.08 million deaths in 2019. In Belgium, one in three men and one in four women will be diagnosed with cancer before the age of 75 years. Cancer is a group of diseases that occurs when abnormal cells from any part of the body begin to grow uncontrollably. Cancer cells combined with non-cancer cells form a mass called a tumour, with a tumour microenvironment. Cancer can spread and invade surrounding tissues or even move to another part of the body to form metastases that are the main cause of cancer death. Prostate cancer is the most common cancer in men in terms of prevalence. It is also the most diagnosed cancer in men in 2020, with 1.41 million new cases. Most of the patients have a 5-year survival rate above 90%. However, this rate drops to only 20% in case of more aggressive and metastatic prostate cancer. While many cancer cells rely on the extensive use of glucose as a source of energy and building blocks to sustain cell proliferation, prostate cancer cells rely on other substrates than glucose, particularly on exogeneous fatty acids to produce energy through β-oxidation. Exogeneous fatty acids have also been shown to be the main source of intracellular lipids, accounting for 83% of the total cell lipids. This hallmark of prostate cancer makes it a potential target for therapy. Among the fatty acids, conjugated linolenic acids (CLnAs) have been identified as molecules with potent anticancer properties, one isomer being punicic acid (PunA, c18:3 c9t11c13). PunA cytotoxicity was studied alone and in combinations with one of several standard fatty acids (stearic (STE), oleic (OLE), linoleic (LA), α-linolenic (ALA), eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids) in 22Rv1 and PC3 prostate cancer cell lines. Viability tests show that PunA is cytotoxic in both prostate cells, and especially, in PC3 cells. This cytotoxicity is altered by the addition of another fatty acid to PunA. The added fatty acids have an inherent influence on the viability of these cells while in combination, their impact is different and depends on their structure. STE, OLE and LA decrease PunA cytotoxicity in both cell lines. ALA and EPA inhibit PunA cytotoxicity in 22Rv1 cells whereas they amplify it in PC3 cells. A synergic cytotoxic effect appears when PunA is combined to DHA in both cell lines. Lipid peroxidation experiments highlight the production of lipid peroxides when PunA is added in PC3 cells, confirming the cell death by ferroptosis induced by PunA-triggered lipid peroxidation. However, in 22Rv1 cells, lipid peroxidation does not occur with short-term treatments, probably due to the expression of the antioxidant enzyme GPX4 that converts lipid peroxides into their respective alcohols. However, the impact of the combined fatty acids is not explained by changes in lipid peroxidation, as no difference in lipid peroxidation was observed. It can be explained by their intrinsic cytotoxicity as well as by a lower rate of lipid peroxidation of the added fatty acids compared to PunA. The fatty acid profiles point out that PunA enrichment is not the explanation for the differences in fatty acid-induced cytotoxicity between the two cell lines. However, the total lipid composition of cells could explain the cytotoxicity. The changes observed in the proportions of the different fatty acid families in the neutral lipids (saturated, monounsaturated and polyunsaturated fatty acids) and the individual nature of each fatty acid present in cells may justify the differences in cell viability. This Master’s thesis proposes that the combination of PunA with a fatty acid, which may be present in the diet or in the blood, may alter PunA impact in the fight against cancer cells. It highlights new questions about the interactions of a CLnA with several compounds in a more complex environment such as in the tumour microenvironment in vivo. If these interactions are confirmed, an additive to PunA could be administered to patients to counteract the inhibitory effect of some fatty acids or to further enhance the effect of CLnAs through combinations with polyunsaturated fatty acids.