Suppression of Extracellular Signal-related Kinase and Activation of p38 MAPK Are Two Critical Events Leading to Caspase-8- and Mitochondria-mediated Cell Death in Phytosphingosine-treated Human Cancer Cells

Moon Taek Park, Jung A. Choi, Min Jeong Kim, Hong Duck Um, Sangwoo Bae, Chang M. Kang, Chul K. Cho, Seong Man Kang, Hee Yong Chung, Yun S. Lee, Su J. Lee

Research output: Contribution to journalArticle

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Abstract

We previously demonstrated that the phytosphingosine-induced apoptosis was accompanied by the concomitant induction of both the caspase-8-mediated and mitochondrial activation-mediated apoptosis pathways. In the present study, we investigated the role of mitogen-activated protein kinases (MAPKs) in the activation of these two distinct cell death pathways induced by phytosphingosine in human cancer cells. Phytosphingosine caused strong induction of caspase-8 activity and caspase-independent Bax translocation to the mitochondria. A rapid decrease of phosphorylated ERK1/2 and a marked increase of p38 MAPK phosphorylation were observed within 10 min after phytosphingosine treatment. Activation of ERK1/2 by pretreatment with phorbol 12-myristate 13-acetate or forced expression of ERK1/2 attenuated phytosphingosine-induced caspase-8 activation. However, Bax translocation and caspase-9 activation was unaffected, indicating that down-regulation of the ERK activity is specifically required for the phytosphingosine-induced caspase-8-dependent cell death pathway. On the other hand, treatment with SB203580, a p38 MAPK-specific inhibitor, or expression of a dominant negative form of p38 MAPK suppressed phytosphingosine-induced translocation of the proapoptotic protein, Bax, from the cytosol to mitochondria, cytochrome c release, and subsequent caspase-9 activation but did not affect caspase-8 activation, indicating that activation of p38 MAPK is involved in the mitochondrial activation-mediated cell death pathway. Our results suggest that phytosphingosine can utilize two different MAPK signaling pathways for amplifying the apoptosis cascade, enhancing the understanding of the molecular mechanisms utilized by naturally occurring metabolites to regulate cell death. Molecular dissection of the signaling pathways that activate the apoptotic cell death machinery is critical for both our understanding of cell death events and development of cancer therapeutic agents.

Original languageEnglish
Pages (from-to)50624-50634
Number of pages11
JournalJournal of Biological Chemistry
Volume278
Issue number50
DOIs
Publication statusPublished - 2003 Dec 12

Fingerprint

phytosphingosine
Mitochondria
Caspase 8
p38 Mitogen-Activated Protein Kinases
Cell death
Cell Death
Phosphotransferases
Chemical activation
Cells
Neoplasms
Caspase 9
Apoptosis
Mitogen-Activated Protein Kinases
bcl-2-Associated X Protein
Dissection
Phosphorylation
Protein Transport
Protein Kinase Inhibitors
Caspases
Cytochromes c

ASJC Scopus subject areas

  • Biochemistry

Cite this

Suppression of Extracellular Signal-related Kinase and Activation of p38 MAPK Are Two Critical Events Leading to Caspase-8- and Mitochondria-mediated Cell Death in Phytosphingosine-treated Human Cancer Cells. / Park, Moon Taek; Choi, Jung A.; Kim, Min Jeong; Um, Hong Duck; Bae, Sangwoo; Kang, Chang M.; Cho, Chul K.; Kang, Seong Man; Chung, Hee Yong; Lee, Yun S.; Lee, Su J.

In: Journal of Biological Chemistry, Vol. 278, No. 50, 12.12.2003, p. 50624-50634.

Research output: Contribution to journalArticle

Park, Moon Taek ; Choi, Jung A. ; Kim, Min Jeong ; Um, Hong Duck ; Bae, Sangwoo ; Kang, Chang M. ; Cho, Chul K. ; Kang, Seong Man ; Chung, Hee Yong ; Lee, Yun S. ; Lee, Su J. / Suppression of Extracellular Signal-related Kinase and Activation of p38 MAPK Are Two Critical Events Leading to Caspase-8- and Mitochondria-mediated Cell Death in Phytosphingosine-treated Human Cancer Cells. In: Journal of Biological Chemistry. 2003 ; Vol. 278, No. 50. pp. 50624-50634.
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abstract = "We previously demonstrated that the phytosphingosine-induced apoptosis was accompanied by the concomitant induction of both the caspase-8-mediated and mitochondrial activation-mediated apoptosis pathways. In the present study, we investigated the role of mitogen-activated protein kinases (MAPKs) in the activation of these two distinct cell death pathways induced by phytosphingosine in human cancer cells. Phytosphingosine caused strong induction of caspase-8 activity and caspase-independent Bax translocation to the mitochondria. A rapid decrease of phosphorylated ERK1/2 and a marked increase of p38 MAPK phosphorylation were observed within 10 min after phytosphingosine treatment. Activation of ERK1/2 by pretreatment with phorbol 12-myristate 13-acetate or forced expression of ERK1/2 attenuated phytosphingosine-induced caspase-8 activation. However, Bax translocation and caspase-9 activation was unaffected, indicating that down-regulation of the ERK activity is specifically required for the phytosphingosine-induced caspase-8-dependent cell death pathway. On the other hand, treatment with SB203580, a p38 MAPK-specific inhibitor, or expression of a dominant negative form of p38 MAPK suppressed phytosphingosine-induced translocation of the proapoptotic protein, Bax, from the cytosol to mitochondria, cytochrome c release, and subsequent caspase-9 activation but did not affect caspase-8 activation, indicating that activation of p38 MAPK is involved in the mitochondrial activation-mediated cell death pathway. Our results suggest that phytosphingosine can utilize two different MAPK signaling pathways for amplifying the apoptosis cascade, enhancing the understanding of the molecular mechanisms utilized by naturally occurring metabolites to regulate cell death. Molecular dissection of the signaling pathways that activate the apoptotic cell death machinery is critical for both our understanding of cell death events and development of cancer therapeutic agents.",
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T1 - Suppression of Extracellular Signal-related Kinase and Activation of p38 MAPK Are Two Critical Events Leading to Caspase-8- and Mitochondria-mediated Cell Death in Phytosphingosine-treated Human Cancer Cells

AU - Park, Moon Taek

AU - Choi, Jung A.

AU - Kim, Min Jeong

AU - Um, Hong Duck

AU - Bae, Sangwoo

AU - Kang, Chang M.

AU - Cho, Chul K.

AU - Kang, Seong Man

AU - Chung, Hee Yong

AU - Lee, Yun S.

AU - Lee, Su J.

PY - 2003/12/12

Y1 - 2003/12/12

N2 - We previously demonstrated that the phytosphingosine-induced apoptosis was accompanied by the concomitant induction of both the caspase-8-mediated and mitochondrial activation-mediated apoptosis pathways. In the present study, we investigated the role of mitogen-activated protein kinases (MAPKs) in the activation of these two distinct cell death pathways induced by phytosphingosine in human cancer cells. Phytosphingosine caused strong induction of caspase-8 activity and caspase-independent Bax translocation to the mitochondria. A rapid decrease of phosphorylated ERK1/2 and a marked increase of p38 MAPK phosphorylation were observed within 10 min after phytosphingosine treatment. Activation of ERK1/2 by pretreatment with phorbol 12-myristate 13-acetate or forced expression of ERK1/2 attenuated phytosphingosine-induced caspase-8 activation. However, Bax translocation and caspase-9 activation was unaffected, indicating that down-regulation of the ERK activity is specifically required for the phytosphingosine-induced caspase-8-dependent cell death pathway. On the other hand, treatment with SB203580, a p38 MAPK-specific inhibitor, or expression of a dominant negative form of p38 MAPK suppressed phytosphingosine-induced translocation of the proapoptotic protein, Bax, from the cytosol to mitochondria, cytochrome c release, and subsequent caspase-9 activation but did not affect caspase-8 activation, indicating that activation of p38 MAPK is involved in the mitochondrial activation-mediated cell death pathway. Our results suggest that phytosphingosine can utilize two different MAPK signaling pathways for amplifying the apoptosis cascade, enhancing the understanding of the molecular mechanisms utilized by naturally occurring metabolites to regulate cell death. Molecular dissection of the signaling pathways that activate the apoptotic cell death machinery is critical for both our understanding of cell death events and development of cancer therapeutic agents.

AB - We previously demonstrated that the phytosphingosine-induced apoptosis was accompanied by the concomitant induction of both the caspase-8-mediated and mitochondrial activation-mediated apoptosis pathways. In the present study, we investigated the role of mitogen-activated protein kinases (MAPKs) in the activation of these two distinct cell death pathways induced by phytosphingosine in human cancer cells. Phytosphingosine caused strong induction of caspase-8 activity and caspase-independent Bax translocation to the mitochondria. A rapid decrease of phosphorylated ERK1/2 and a marked increase of p38 MAPK phosphorylation were observed within 10 min after phytosphingosine treatment. Activation of ERK1/2 by pretreatment with phorbol 12-myristate 13-acetate or forced expression of ERK1/2 attenuated phytosphingosine-induced caspase-8 activation. However, Bax translocation and caspase-9 activation was unaffected, indicating that down-regulation of the ERK activity is specifically required for the phytosphingosine-induced caspase-8-dependent cell death pathway. On the other hand, treatment with SB203580, a p38 MAPK-specific inhibitor, or expression of a dominant negative form of p38 MAPK suppressed phytosphingosine-induced translocation of the proapoptotic protein, Bax, from the cytosol to mitochondria, cytochrome c release, and subsequent caspase-9 activation but did not affect caspase-8 activation, indicating that activation of p38 MAPK is involved in the mitochondrial activation-mediated cell death pathway. Our results suggest that phytosphingosine can utilize two different MAPK signaling pathways for amplifying the apoptosis cascade, enhancing the understanding of the molecular mechanisms utilized by naturally occurring metabolites to regulate cell death. Molecular dissection of the signaling pathways that activate the apoptotic cell death machinery is critical for both our understanding of cell death events and development of cancer therapeutic agents.

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