title: Mechanisms of ceramide-induced COX-2-dependent apoptosis in human ovarian cancer OVCAR-3 cells partially overlapped with resveratrol.
abstract: Ceramide is a member of the sphingolipid family of bioactive molecules demonstrated to have profound, diverse biological activities. Ceramide is a potential chemotherapeutic agent via the induction of apoptosis. Exposure to ceramide activates extracellular-signal-regulated kinases (ERK)1/2- and p38 kinase-dependent apoptosis in human ovarian cancer OVCAR-3 cells, concomitant with an increase in the expression of COX-2 and p53 phosphorylation. Blockade of cyclooxygenase-2 (COX-2) activity by siRNA or NS398 correspondingly inhibited ceramide-induced p53 Ser-15 phosphorylation and apoptosis; thus COX-2 appears at the apex of the p38 kinase-mediated signaling cascade induced by ceramide. Induction of apoptosis by ceramide or resveratrol was inhibited by the endocytosis inhibitor, cytochalasin D (CytD); however, cells exposed to resveratrol showed greater sensitivity than ceramide-treated cells. Ceramide-treated cells underwent a dose-dependent reduction in trans-membrane potential. Although both ceramide and resveratrol induced the expressions of caspase-3 and -7, the effect of inducible COX-2 was different in caspase-7 expression induced by ceramide compared to resveratrol. In summary, resveratrol and ceramide converge on an endocytosis-requiring, ERK1/2-dependent signal transduction pathway and induction of COX-expression as an essential molecular antecedent for subsequent p53-dependent apoptosis. In addition, expressions of caspase-3 and -7 are observed. However, a p38 kinase-dependent signal transduction pathway and change in mitochondrial potential are also involved in ceramide-induced apoptosis.
authors.affiliation: Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan. linhy@tmu.edu.tw
authors.forename: Hung-Yun
authors.initials: HY
authors.lastname: Lin
authors.forename: Dominique
authors.initials: D
authors.lastname: Delmas
authors.forename: Ole
authors.initials: O
authors.lastname: Vang
authors.forename: Tze-Chen
authors.initials: TC
authors.lastname: Hsieh
authors.forename: Sharon
authors.initials: S
authors.lastname: Lin
authors.forename: Guei-Yun
authors.initials: GY
authors.lastname: Cheng
authors.forename: Hsiao-Ling
authors.initials: HL
authors.lastname: Chiang
authors.forename: Chiao En
authors.initials: CE
authors.lastname: Chen
authors.forename: Heng-Yuan
authors.initials: HY
authors.lastname: Tang
authors.forename: Dana R
authors.initials: DR
authors.lastname: Crawford
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Whang-Peng
authors.forename: Jaulang
authors.initials: J
authors.lastname: Hwang
authors.forename: Leroy F
authors.initials: LF
authors.lastname: Liu
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Wu
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053179:Caspase 7 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002518:Ceramides / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000235:genetics; D009578:Nitrobenzenes / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D034741:RNA, Small Interfering; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002518:Ceramides; D009578:Nitrobenzenes; D034741:RNA, Small Interfering; D013267:Stilbenes; D013449:Sulfonamides; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D048051:p38 Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7; D000077185:Resveratrol