title: Arachidonic acid metabolism via cytosolic phospholipase A2 α 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.
authors.affiliation: Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Chuo-ku, Chiba, Japan. nakahiro@faculty.chiba-u.jp
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakamura
authors.forename: Kana
authors.initials: K
authors.lastname: Yasufuku
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Makiyama
authors.forename: Ikiru
authors.initials: I
authors.lastname: Matsumoto
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Fujino
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Murayama
mesh_terms: D000736:Androstenes / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D016466:CHO Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism; D006224:Cricetinae; D051545:Cyclooxygenase 1 / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000235:genetics; D003600:Cytosol / Q000378:metabolism; D015232:Dinoprostone / Q000096:biosynthesis; D005354:Fibrosarcoma / Q000235:genetics / Q000378:metabolism; D054513:Group IV Phospholipases A2 / Q000235:genetics* / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D052556:Niemann-Pick Disease, Type C / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000736:Androstenes; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; D016718:Arachidonic Acid; C006261:3-beta-(2-(diethylamino)ethoxy)androst-5-en-17-one; D002784:Cholesterol; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D054513:Group IV Phospholipases A2; D015232:Dinoprostone