Mechanisms of ceramide-induced COX-2-dependent apoptosis in human ovarian cancer OVCAR-3 cells partially overlapped with resveratrol†
Corresponding Author
Hung-Yun Lin
Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan
Institute of Cancer Biology and Drug Discovery, Taipei Medical University, 250 Wu-Hsing Street, Taipei, Taiwan.Search for more papers by this authorDominique Delmas
Université de Bourgogne, Faculté de Médecine, Dijon, Bourgogne, France
INSERM U866 “Chemotherapy, Lipid Metabolism and Antitumoral Immune Response”, Dijon, Bourgogne, France
Search for more papers by this authorOle Vang
Department of Science, Systems and Models, Roskilde University, Roskilde, Denmark
Search for more papers by this authorTze-Chen Hsieh
Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, New York
Search for more papers by this authorSharon Lin
Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, New York
Search for more papers by this authorGuei-Yun Cheng
Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan
Search for more papers by this authorHsiao-Ling Chiang
Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan
Search for more papers by this authorChiao En Chen
Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan
Search for more papers by this authorHeng-Yuan Tang
Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, New York
Search for more papers by this authorDana R. Crawford
Center for Immunology & Microbial Disease, Albany Medical College, Albany, New York
Search for more papers by this authorJacqueline Whang-Peng
Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan
Search for more papers by this authorJaulang Hwang
Department of Biochemistry, School of Medicine, Taipei Medical University, Taipei, Taiwan
Search for more papers by this authorLeroy F. Liu
Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan
Department of Pharmacology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey
Search for more papers by this authorJoseph M. Wu
Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, New York
Search for more papers by this authorCorresponding Author
Hung-Yun Lin
Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan
Institute of Cancer Biology and Drug Discovery, Taipei Medical University, 250 Wu-Hsing Street, Taipei, Taiwan.Search for more papers by this authorDominique Delmas
Université de Bourgogne, Faculté de Médecine, Dijon, Bourgogne, France
INSERM U866 “Chemotherapy, Lipid Metabolism and Antitumoral Immune Response”, Dijon, Bourgogne, France
Search for more papers by this authorOle Vang
Department of Science, Systems and Models, Roskilde University, Roskilde, Denmark
Search for more papers by this authorTze-Chen Hsieh
Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, New York
Search for more papers by this authorSharon Lin
Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, New York
Search for more papers by this authorGuei-Yun Cheng
Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan
Search for more papers by this authorHsiao-Ling Chiang
Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan
Search for more papers by this authorChiao En Chen
Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan
Search for more papers by this authorHeng-Yuan Tang
Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, New York
Search for more papers by this authorDana R. Crawford
Center for Immunology & Microbial Disease, Albany Medical College, Albany, New York
Search for more papers by this authorJacqueline Whang-Peng
Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan
Search for more papers by this authorJaulang Hwang
Department of Biochemistry, School of Medicine, Taipei Medical University, Taipei, Taiwan
Search for more papers by this authorLeroy F. Liu
Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan
Department of Pharmacology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey
Search for more papers by this authorJoseph M. Wu
Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, New York
Search for more papers by this authorDisclosure statement: Dr. Ole Vang is the consultant for Fluxome A/S; none of the other authors have a financial interest in the subject of this article.
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. J. Cell. Biochem. 114: 1940–1954, 2013. © 2013 Wiley Periodicals, Inc.
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