Mechanisms of ceramide-induced COX-2-dependent apoptosis in human ovarian cancer OVCAR-3 cells partially overlapped with resveratrol

Hung-Yun Lin, Dominique Delmas, Ole Vang, Tze-Chen Hsieh, Sharon Lin , Guei-Yun Cheng, Hsiao-Ling Chiang , Chiao En Chen , Heng-Yuan Tang, Dana Crawford, Jacqueline Whang-Peng, Jaulang Hwang, Leroy Liu, Joseph Wu

    Publikation: Bidrag til tidsskriftTidsskriftartikelpeer review

    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.
    OriginalsprogEngelsk
    TidsskriftJournal of Cellular Biochemistry
    Vol/bind114
    Udgave nummer8
    Sider (fra-til)1940-1954
    ISSN0730-2312
    DOI
    StatusUdgivet - 2013

    Emneord

    • ceramide
    • resveratrol
    • COX-2
    • p53
    • p38 kinase
    • apoptosis

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