Oxidized unsaturated fatty acids induce apoptotic cell death in cultured cells

Abstract

Polyunsaturated fatty acids are oxidized by non-enzymatic or enzymatic reactions. The oxidized products are multifunctional. In this study, we investigated how oxidized fatty acids inhibit cell proliferation in cultured cells. We used polyunsaturated and saturated fatty acids, docosahexaenoic acid (DHA; 22:6), eicosapentaenoic acid (EPA; 20:5), linoleic acid (LA; 18:2), and palmitic acid (16:0). Oxidized fatty acids were produced by autoxidation of fatty acids for 2 days in the presence of a gas mixture (20% O2 and 80% N2). We found that oxidized polyunsaturated fatty acids (OxDHA, OxEPA and OxLA) inhibited cell proliferation much more effectively compared with un-oxidized fatty acids (DHA, EPA and LA, respectively) in THP-1 (a human monocytic leukemia cell line) and DLD-1 (a human colorectal cancer cell line) cells. In particular, OxDHA markedly inhibited cell proliferation. DHA has the largest number of double bonds and is most susceptible to oxidation among the fatty acids. OxDHA has the largest number of highly active oxidized products. Therefore, the oxidative levels of fatty acids are associated with the anti-proliferative activity. Moreover, caspase-3/7 was activated in the cells treated with OxDHA, but not in those treated with DHA. A pan-caspase inhibitor (zVAD-fmk) reduced the cell death induced by OxDHA. These results indicated that oxidized products from polyunsaturated fatty acids induced apoptosis in cultured cells. Collectively, the switch between cell survival and cell death may be regulated by the activity and/or number of oxidized products from polyunsaturated fatty acids.

The role of oxidised self-lipids and alveolar macrophage CD1b expression in COPD

“…Pasini et al found elevated lysophosphotidylcholine in the plasma of smokers vs never-smokers and that exposure to oxidised lipids increased the level of lysophosphotidylcholine in never-smoker PBMCs 78 . Oxidised lipids are also known to induce apoptosis in cells 79 , 80 and in this study we showed that CS-oxidised lipids were able to induce bronchial epithelial cell necrosis and apoptosis. Thus, the authors suggest that smoking results in increased lysophosphotidylcholine and oxidised lipids in the airways from apoptotic epithelial cells which in turn may trigger further apoptosis of cells in the airways as well as inflammation, contributing to a vicious cycle of ongoing airway cell apoptosis even after smoking may have ceased, something that is documented to occur in COPD ex-smoker patients 12 , 77 .…”

Connecting lysosomes and mitochondria – a novel role for lipid metabolism in cancer cell death

“…It was even reported that there is a differential role of saturated and unsaturated fatty acids, whereas unsaturated fatty acids influence autophagy but do not promote apoptosis, saturated fatty acids suppress autophagy and induce apoptosis [39]. However, other studies found that unsaturated lipids can induce apoptotic cell death, especially when peroxidized [40,41]. We conclude that the observed changes in lipid composition caused by disruption of lysosomal function lead to a change in mitochondrial membrane composition, which on the one hand impairs mitochondrial function and on the other, triggers release of cytochrome C to the cytosol and subsequently induces apoptosis.…”

Lipid composition of the cancer cell membrane

“…Unsaturated bonds in the hydrocarbon chains of phosphatidylethanolamine are susceptible to ROS-mediated oxidation (Iuchi et al, 2019). The process is tightly connected with ferroptosis -a type of cell death, induced by the accumulation of lipid peroxides in the membrane (Conrad et al, 2018).…”