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Research ArticleArticle

Involvement of c-Jun NH2-Terminal Kinase Activation and c-Jun in the Induction of Apoptosis by the Ether Phospholipid 1-O-Octadecyl-2-O-methyl-rac-glycero-3-phosphocholine

Consuelo Gajate, Antonio Santos-Beneit, Manuel Modolell and Faustino Mollinedo
Molecular Pharmacology April 1998, 53 (4) 602-612; DOI: https://doi.org/10.1124/mol.53.4.602
Consuelo Gajate
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Antonio Santos-Beneit
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Manuel Modolell
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Faustino Mollinedo
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Abstract

The ether phospholipid 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (ET-18-OCH3; edelfosine) is a potent inducer of apoptosis in human tumor cells. We show that ET-18-OCH3-induced apoptosis is associated with activation of the c-Jun NH2-terminal kinase (JNK) signaling. The addition of ET-18-OCH3 to distinct human leukemic cells (HL-60, U937, and Jurkat), which undergo rapid apoptosis on treatment with ET-18-OCH3, induced a dramatic and sustained increase in the of c-jun mRNA level that was associated with activation of activator protein-1 transcription factor. We found that ET-18-OCH3 induced a persistent activation of JNK in HL-60 cells that was detected before the onset of apoptosis, the latter being assessed by DNA fragmentation and by the appearance of phosphatidylserine on the external leaflet of the plasma membrane. The inductions of JNK after HL-60 monocyte/macrophage differentiation and ET-18-OCH3-mediated apoptosis were distinguished by the different activation patterns, transient versus persistent, respectively. ET-18-OCH3 analogues unable to induce apoptosis failed to activate JNK. ET-18-OCH3-dependent JNK activation was not detected in K562 cells, which did not undergo apoptosis on treatment with ET-18-OCH3. Phorbol myristate acetate inhibited both ET-18-OCH3-induced apoptosis and sustained JNK activation; thus, persistent JNK activation by ET-18-OCH3 is associated with the capacity of this ether phospholipid to induce apoptosis. Furthermore, antisense oligonucleotides directed against c-jun blocked ET-18-OCH3-induced apoptosis, indicating a role for c-Jun in this apoptotic response. These data indicate that JNK activation and c-Jun are involved in the induction of apoptosis by ET-18-OCH3.

Footnotes

    • Received August 20, 1997.
    • Accepted December 23, 1997.
  • Send reprint requests to: Dr. Faustino Mollinedo, Laboratory of Signal Transduction and Leukocyte Biology, Instituto de Biologı́a y Genética Molecular, Facultad de Medicina, Consejo Superior de Investigaciones Cientı́ficas-Universidad de Valladolid, C/Ramon y Cajal, 7, E-47005 Valladolid, Spain. E-mail:fmollin{at}med.uva.es

  • This work was supported in part by Grant FIS96/1434 from the Fondo de Investigación Sanitaria, Grant VA71/96 from the Junta de Castilla y León, Grant PB95–0713 from the Dirección General de Investigación Cientı́fica y Técnica, and Grants HA1996–0118 and AI-40/96 from Acciones Integradas Hispano-Alemanas. C.G. is a recipient of a fellowship from the Fondo de Investigación Sanitaria. A.S.-B. is a recipient of a fellowship from the Ministerio de Educación y Cultura of Spain.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 53 (4)
Molecular Pharmacology
Vol. 53, Issue 4
1 Apr 1998
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Research ArticleArticle

Involvement of c-Jun NH2-Terminal Kinase Activation and c-Jun in the Induction of Apoptosis by the Ether Phospholipid 1-O-Octadecyl-2-O-methyl-rac-glycero-3-phosphocholine

Consuelo Gajate, Antonio Santos-Beneit, Manuel Modolell and Faustino Mollinedo
Molecular Pharmacology April 1, 1998, 53 (4) 602-612; DOI: https://doi.org/10.1124/mol.53.4.602

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Research ArticleArticle

Involvement of c-Jun NH2-Terminal Kinase Activation and c-Jun in the Induction of Apoptosis by the Ether Phospholipid 1-O-Octadecyl-2-O-methyl-rac-glycero-3-phosphocholine

Consuelo Gajate, Antonio Santos-Beneit, Manuel Modolell and Faustino Mollinedo
Molecular Pharmacology April 1, 1998, 53 (4) 602-612; DOI: https://doi.org/10.1124/mol.53.4.602
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