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J. Biol. Chem., Vol. 278, Issue 8, 5574-5583, February 21, 2003
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From the Center of Excellence on Neurodegenerative Diseases, Study
Center for the Biochemistry and Biotechnology of Glycolipids,
Department of Medical Chemistry, Biochemistry and Biotechnology,
University of Milan, 20090 Segrate, Italy and the
In the present work, we studied the effects of
fenretinide (N-(4-hydroxyphenyl)retinamide (HPR)), a
hydroxyphenyl derivative of all-trans-retinoic acid, on
sphingolipid metabolism and expression in human ovarian carcinoma A2780
cells. A2780 cells, which are sensitive to a pharmacologically
achievable HPR concentration, become 10-fold more resistant after
exposure to increasing HPR concentrations. Our results showed that HPR
was able to induce a dose- and time-dependent increase in
cellular ceramide levels in sensitive but not in resistant cells. This
form of resistance in A2780 cells was not accompanied by the
overexpression of multidrug resistance-specific proteins MDR1
P-glycoprotein and multidrug resistance-associated protein,
whose mRNA levels did not differ in sensitive and resistant A2780
cells. HPR-resistant cells were characterized by an overall altered
sphingolipid metabolism. The overall content in glycosphingolipids was
similar in both cell types, but the expression of specific
glycosphingolipids was different. Specifically, our findings
indicated that glucosylceramide levels were similar in sensitive and
resistant cells, but resistant cells were characterized by a 6-fold
lower expression of lactosylceramide levels and by a 6-fold higher
expression of ganglioside levels than sensitive cells. The main
gangliosides from resistant A2780 cells were identified as GM3 and GM2.
The possible metabolic mechanisms leading to this difference were
investigated. Interestingly, the mRNA levels of glucosylceramide
and lactosylceramide synthases were similar in sensitive and resistant
cells, whereas GM3 synthase mRNA level and GM3 synthase activity
were remarkably higher in resistant cells.
Altered Sphingolipid Metabolism in
N-(4-Hydroxyphenyl)- retinamide-resistant A2780 Human
Ovarian Carcinoma Cells*
,,,, and Department of Experimental Oncology, Istituto Nazionale
Tumori, 20133 Milan, Italy
*
This work was supported by COFIN-PRIN Grants 2000 and 2001, Consiglio Nazionale delle Ricerche (PF Biotechnology), Italy, and
Mizutani Foundation for Glycoscience Grant 2002 (to S. S.), and by
Associazione Italiana per la Ricerca sul Cancro (to F. F.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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