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: 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 R Crawford, Jacqueline Whang-Peng, Jaulang Hwang, Leroy F Liu, Joseph M Wu
• Journal: Journal of cellular biochemistry (J Cell Biochem) Vol. 114 Issue 8 Pg. 1940-54 (Aug 2013) ISSN: 1097-4644 [Electronic] United States
• PMID: 23495037 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Wiley Periodicals, Inc.

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Ceramides
• Nitrobenzenes
• RNA, Small Interfering
• Stilbenes
• Sulfonamides
• TP53 protein, human
• Tumor Suppressor Protein p53
• N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
• Cyclooxygenase 2
• PTGS2 protein, human
• p38 Mitogen-Activated Protein Kinases
• CASP3 protein, human
• CASP7 protein, human
• Caspase 3
• Caspase 7
• Resveratrol

Topics

• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Apoptosis (drug effects, genetics)
• Caspase 3 (genetics, metabolism)
• Caspase 7 (genetics, metabolism)
• Cell Line, Tumor
• Ceramides (genetics, metabolism, pharmacology)
• Cyclooxygenase 2 (genetics, metabolism)
• Female
• Gene Expression Regulation, Enzymologic (drug effects, genetics)
• Gene Expression Regulation, Neoplastic (drug effects, genetics)
• Humans
• MAP Kinase Signaling System (drug effects)
• Membrane Potential, Mitochondrial (drug effects, genetics)
• Nitrobenzenes (pharmacology)
• Ovarian Neoplasms (drug therapy, genetics, metabolism, pathology)
• Phosphorylation (drug effects, genetics)
• RNA, Small Interfering
• Resveratrol
• Stilbenes (pharmacology)
• Sulfonamides (pharmacology)
• Tumor Suppressor Protein p53 (genetics, metabolism)
• p38 Mitogen-Activated Protein Kinases (genetics, metabolism)