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 R. Crawford, Jacqueline Whang-Peng, Jaulang Hwang, Leroy F. Liu, Joseph M. Wu

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)1940-1954
Number of pages15
JournalJournal of Cellular Biochemistry
Volume114
Issue number8
DOIs
Publication statusPublished - Aug 2013

Fingerprint

Ceramides
Cyclooxygenase 2
Ovarian Neoplasms
Apoptosis
Caspase 7
Signal transduction
Phosphorylation
Phosphotransferases
Endocytosis
Caspase 3
resveratrol
Signal Transduction
Cells
Cytochalasin D
Sphingolipids
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Bioactivity
Membrane Potentials
Small Interfering RNA

Keywords

  • APOPTOSIS
  • CERAMIDE
  • COX-2
  • p38 KINASE
  • p53
  • RESVERATROL

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Mechanisms of ceramide-induced COX-2-dependent apoptosis in human ovarian cancer OVCAR-3 cells partially overlapped with resveratrol. / Lin, Hung Yun; Delmas, Dominique; Vang, Ole; Hsieh, Tze Chen; Lin, Sharon; Cheng, Guei Yun; Chiang, Hsiao Ling; Chen, Chiao En; Tang, Heng Yuan; Crawford, Dana R.; Whang-Peng, Jacqueline; Hwang, Jaulang; Liu, Leroy F.; Wu, Joseph M.

In: Journal of Cellular Biochemistry, Vol. 114, No. 8, 08.2013, p. 1940-1954.

Research output: Contribution to journalArticle

Lin, HY, Delmas, D, Vang, O, Hsieh, TC, Lin, S, Cheng, GY, Chiang, HL, Chen, CE, Tang, HY, Crawford, DR, Whang-Peng, J, Hwang, J, Liu, LF & Wu, JM 2013, 'Mechanisms of ceramide-induced COX-2-dependent apoptosis in human ovarian cancer OVCAR-3 cells partially overlapped with resveratrol', Journal of Cellular Biochemistry, vol. 114, no. 8, pp. 1940-1954. https://doi.org/10.1002/jcb.24539
Lin, Hung Yun ; Delmas, Dominique ; Vang, Ole ; Hsieh, Tze Chen ; Lin, Sharon ; Cheng, Guei Yun ; Chiang, Hsiao Ling ; Chen, Chiao En ; Tang, Heng Yuan ; Crawford, Dana R. ; Whang-Peng, Jacqueline ; Hwang, Jaulang ; Liu, Leroy F. ; Wu, Joseph M. / Mechanisms of ceramide-induced COX-2-dependent apoptosis in human ovarian cancer OVCAR-3 cells partially overlapped with resveratrol. In: Journal of Cellular Biochemistry. 2013 ; Vol. 114, No. 8. pp. 1940-1954.
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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.",
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AU - Lin, Hung Yun

AU - Delmas, Dominique

AU - Vang, Ole

AU - Hsieh, Tze Chen

AU - Lin, Sharon

AU - Cheng, Guei Yun

AU - Chiang, Hsiao Ling

AU - Chen, Chiao En

AU - Tang, Heng Yuan

AU - Crawford, Dana R.

AU - Whang-Peng, Jacqueline

AU - Hwang, Jaulang

AU - Liu, Leroy F.

AU - Wu, Joseph M.

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N2 - 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.

AB - 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.

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