HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 18, 18256-18261, April 30, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/18/18256    most recent M314105200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Grazide, S. Articles by Jaffrézou, J.-P. Search for Related Content PubMed PubMed Citation Articles by Grazide, S. Articles by Jaffrézou, J.-P. Social Bookmarking                      What's this?

Cytoprotective Effect of Glucosylceramide Synthase Inhibition against Daunorubicin-induced Apoptosis in Human Leukemic Cell Lines^*

Solène Grazide¶, Anne-Dominique Terrisse, Sandra Lerouge, Guy Laurent||, and Jean-Pierre Jaffrézou**

From the INSERM U563-Centre de Physiopathologie Toulouse Purpan, Institut Claudius Régaud, Toulouse 31052, and the ^||Service d'Hématologie, Centre Hospitalier Universitaire Purpan, Toulouse 31059, France

Several studies have shown that ceramide (CER) glucosylation contributes to drug resistance in multidrug-resistant cells and that inhibition of glucosylceramide synthase sensitizes cells to various drug treatments. However, the role of glucosylceramide synthase has not been studied in drug-sensitive cancer cells. We have demonstrated previously that the anthracycline daunorubicin (DNR) rapidly induces interphasic apoptosis through neutral sphingomyelinase-mediated CER generation in human leukemic cell lines. We now report that inhibition of glucosylceramide synthase using D,L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) or 1-phenyl-2-palmitoylamino-3-morpholino-1-propanol (PPMP) protected U937 and HL-60 cells from DNR-induced apoptosis. Moreover, blocking CER glucosylation did not lead to increased CER levels but to increased CER galactosylation. We also observed that pretreating cells with galactosylceramide (GalCER) significantly inhibited DNR-induced apoptosis. Finally, we show that GalCER-enriched lymphoblast cells (Krabbe's disease) were significantly more resistant to DNR- and cytosine arabinoside-induced apoptosis as compared with normal lymphoblasts, whereas glucosylceramide-enriched cells (Gaucher's disease) were more sensitive. In conclusion, this study suggests that sphingomyelin-derived CER in itself is not a second messenger but rather a precursor of both an apoptosis second messenger (GD3) and an apoptosis "protector" (GalCER).

Received for publication, December 23, 2003 , and in revised form, February 6, 2004.

^* This work was supported by la Ligue Nationale Contre le Cancer and les Comités Départementaux du Gers, de l'Aveyron, de la Haute-Garonne (to J.-P. J.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

^¶ Recipient of a grant from la Fondation pour la Recherche Médicale.

^** To whom correspondence should be addressed: INSERM U563-CPTP, Institut Claudius Régaud, 20 rue du Pont-St. Pierre, Toulouse 31059, France. Tel.: 33-5-61-42-41-73; Fax: 33-5-61-42-46-06; E-mail: jaffrezou{at}icr.fnclcc.fr.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				A. Charruyer, S. M. Bell, M. Kawano, S. Douangpanya, T.-Y. Yen, B. A. Macher, K. Kumagai, K. Hanada, W. M. Holleran, and Y. Uchida Decreased Ceramide Transport Protein (CERT) Function Alters Sphingomyelin Production following UVB Irradiation J. Biol. Chem., June 13, 2008; 283(24): 16682 - 16692. [Abstract] [Full Text] [PDF]

				B. Monzavi-Karbassi, C. Artaud, F. Jousheghany, L. Hennings, J. Carcel-Trullols, S. Shaaf, S. Korourian, and T. Kieber-Emmons Reduction of Spontaneous Metastases through Induction of Carbohydrate Cross-Reactive Apoptotic Antibodies J. Immunol., June 1, 2005; 174(11): 7057 - 7065. [Abstract] [Full Text] [PDF]