Lipoxygenases and their involvement in programmed cell death

Abstract

Lipoxygenases are a family of enzymes which dioxygenate unsaturated fatty acids, thus initiating lipoperoxidation of membranes and the synthesis of signaling molecules. Consequently, they induce structural and metabolic changes in the cell in a number of pathophysiological conditions. Recently, a pro-apoptotic effect of lipoxygenase, and of the hydroperoxides produced thereof, has been reported in different cells and tissues, leading to cell death. Anti-apoptotic effects of lipoxygenases have also been reported; however, this has often been based on the use of enzyme inhibitors. Here we review the characteristics of the lipoxygenase family and its involvement in the initiation of oxidative stress-induced apoptosis. Finally, we discuss the role of lipoxygenase activation in apoptosis of animal and plant cells, suggesting a common signal transduction pathway in cell death conserved through evolution of both kingdoms. Cell Death and Differentiation (2001) 8, 776 ± 784.

Blockade of 12-lipoxygenase expression protects cortical neurons from apoptosis induced by β-amyloid peptide

“…25,26 However, the protection afforded by 12-LOX blockade against Ab-induced apoptosis as well as the induction of apoptosis by 12(S)-HETE observed in the present work favored a proapoptotic involvement of this enzyme in cortical cells. These findings add to previous studies showing that 12-LOX mediated apoptosis induced by other stimuli, such as glutamate or BSO, 23 and suggest that this LOX might represent a common intermediate in neurodegenerative processes triggered by various insults.…”

“…As illustrated in Figure 1b, a 24-h treatment of cortical cells with 25 mM Ab [25][26][27][28][29][30][31][32][33][34][35] increased the percentage of apoptotic cells, as assessed by 4 0 ,6-diamidino-2-phenylindole (DAPI) staining. This proapoptotic effect of Ab was totally suppressed by a 48-h pretreatment of the cells with the 12-LOX antisense oligonucleotide, whereas the sense or the scramble 12-LOX oligonucleotide did not show any protective action (Figure 1b).…”

“…32 Using more selective inhibitors, we recently suggested a participation of 12-LOX in apoptosis triggered by Ab in cortical neurons. 33 However, inhibitors can only provide circumstantial evidence about the role of LOXs in Ab-induced toxicity, since most of these compounds also possess other characteristics such as proor antioxidant properties, 25,26,[34][35][36] which might lead to LOX-independent effects. In order to assess the protective potential of 12-LOX blockade towards Ab-induced apoptosis, we used here an antisense oligonucleotide-based strategy.…”

“…21,[46][47][48] Some of them, such as 5-and 12-hydroxyeicosatetraenoic acids, have been reported to exert various actions on neurons, including modulation of Na-K ATPase activity, 49 neurotransmitter release 50 or alteration of membrane potential. 51,52 LOXs also act as regulators of cell proliferation and death, and have been implied in the mediation of apoptosis induced by various physical or chemical agents such as UV light, oxidative stress or receptor ligands 25,26 In contrast, only a small number of studies investigated the involvement of LOXs in the various signaling pathways leading to neurodegeneration. However, data obtained thus far suggest a crucial participation of these enzymes in several of these pathways.…”

“…22,23 LOXs represent important regulators of cell proliferation and death in different cell types. [24][25][26] Moreover, a few studies suggested the involvement of 5-or 12-LOX in pathways leading to neuronal death, such as kainic acid excitotoxicity, 27 apoptosis induced by prion peptide 28 and oxidative glutamate toxicity. 23 In this work, we show that blockade of 12-LOX expression protects cortical neurons from Ab-induced apoptosis, through disruption of a c-Jun-dependent apoptosis pathway.…”