Arachidonic acid metabolism via cytosolic phospholipase A₂α induces cytotoxicity in niemann–pick disease type C cells

Abstract

Niemann-Pick disease type C (NPC) is a neurodegenerative lipid storage disorder caused by mutations in NPC1 or NPC2 genes. Loss of function of either protein results in the endosomal accumulation of cholesterol and other lipids. Here, we report that NPC1-deficient Chinese hamster ovary cells exhibit increased release of arachidonic acid (AA) and synthesis of prostaglandin E(2) compared with wild-type cells. The enhanced release of AA was inhibited by both treatment with the selective inhibitor of cytosolic phospholipase A(2) α (cPLA(2) α) and cultivation in lipoprotein-deficient medium. There was no difference in the expression of both cyclooxygenase-1 and -2 between NPC cells and wild-type cells. U18666A, a cholesterol transport-inhibiting agent commonly used to mimic NPC, also increased the release of AA in L929 mouse fibrosarcoma cells. Furthermore, U18666A-induced formation of reactive oxygen species (ROS) resulted in the induction of cell death and cell cycle delay/arrest in L929 cells. Interestingly, these responses induced by U18666A were much weaker in cPLA(2) α knockdown L929 cells. These results suggest that cPLA(2) α-AA pathway plays important roles in the cytotoxicity and the ROS formation in NPC cells.

An Evaluation of 3-Rhamnosylquercetin, a Glycosylated Form of Quercetin, against the Myotoxic and Edematogenic Effects of sPLA2fromCrotalus durissus terrificus

“…Generally, PLA 2 causes these biological, physiological, and pathological activities through its enzymatic activity, which result in the increased production of arachidonic acid, which is the rate-limiting step in the generation of eicosanoids and platelet activating factors. This effect is caused by increased levels of intracellular arachidonic acid that stimulate the activity of cyclooxygenase 2 [33–35] and induce an increase in free radical peroxides and pro inflammatory cytokines. The increased levels of hydrogen peroxide may therefore lead to an increase in the lipid peroxidation levels, which can lead to cell membrane lesions such as those in skeletal muscle cells.…”

Effects of Hsp90 inhibitors, geldanamycin and its analog, on ceramide metabolism and cytotoxicity in PC12 cells

“…AA metabolism couples with cytotoxicity in various cells including PC12 cells (Doroshenko and Doroshenko, 2007;Kurosawa et al, 2009;Nakamura et al, 2012). The inhibition of Hsp90 produces ROS, which can stimulate AA release via cPLA 2 α's activation (Taniguchi et al, 2006), in various cells including PC12 cells (Fukuyo et al, 2008;Clark et al, 2009).…”

“…However, possible changes in ceramide metabolism have not been elucidated in Hsp90 inhibitor-treated PC12 cells. Arachidonic acid (AA) is another cytotoxic factor in various cells including PC12 cells (Doroshenko and Doroshenko, 2007;Kurosawa et al, 2009;Nakamura et al, 2012). Although AA is released by various pathways, a major enzyme responsible for the stimulus-induced release of AA is group IVA phospholipase A 2 (also known as α-type cytosolic PLA 2 , cPLA 2 α).…”

Role of Cytosolic Phospholipase A2 in Oxidative and Inflammatory Signaling Pathways in Different Cell Types in the Central Nervous System

“…In the CNS, cPLA 2 activation has been implicated in the pathogenesis of a number of neurodegenerative diseases, including experimental autoimmune encephalomyelitis [19, 20], Alzheimer’s disease [21–26], Neimann-Pick disease [27], tumorigenesis [28], stroke [29–31], alcoholism [32, 33] as well as a number of affective disorders [34]. However, few studies have elucidated the extracellular agonists and signaling pathways leading to cPLA 2 activation in these disease conditions.…”