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Originally published In Press as doi:10.1074/jbc.M207729200 on January 6, 2003

J. Biol. Chem., Vol. 278, Issue 11, 9592-9601, March 14, 2003
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Ceramide in Nitric Oxide Inhibition of Glioma Cell Growth
EVIDENCE FOR THE INVOLVEMENT OF CERAMIDE TRAFFIC*

Paola VianiDagger , Paola Giussani, Loredana Brioschi, Rosaria Bassi, Viviana Anelli, Guido Tettamanti, and Laura Riboni

From the Department of Medical Chemistry, Biochemistry and Biotechnology, University of Milan, via Fratelli Cervi 93, Segrate, Milan 20090, Italy

The treatment of C6 glioma cells with the nitric oxide donor, PAPANONOate ((Z)-[N-(3-ammoniopropyl)-N-(n-propyl)amino]diazen-1-ium-1,2-diolate), resulted in a dose-dependent inhibition of cell proliferation. This was associated to a rapid and significant increase of ceramide levels and was mimicked by treatments that augment cellular ceramide. Metabolic experiments with radioactive sphingosine, serine, and choline showed that nitric oxide strongly reduced the utilization of ceramide for the biosynthesis of both sphingomyelin and glucosylceramide. Nevertheless, nitric oxide did not modify the activity of different enzymes of ceramide metabolism. The possibility that nitric oxide impairs the availability of ceramide for sphingolipid biosynthesis was then investigated. The metabolism of N-hexanoyl-[3H]sphingosine demonstrated that nitric oxide did not affect the biosynthesis of N-hexanoyl-[3H]sphingolipids but inhibited the metabolic utilization of long chain [3H]ceramide, synthesized in the endoplasmic reticulum (ER) from the recycled [3H]sphingosine. Moreover, results obtained with fluorescent ceramides, brefeldin A, ATP depletion, as well as in a ceramide transport assay indicate that nitric oxide impairs the traffic of ceramide from ER to Golgi apparatus. All this supports that, in glioma cells, the modulation of ceramide traffic can contribute to the regulation of its intracellular levels and participate in the nitric oxide-activated signaling pathway involved in the control of cell proliferation.

* This work was supported by research grants from the Ministry of the University and Scientific and Technological Research (MURST) ex 60% 1998, 1999 (to P. V.) and MURST Progeltidi Riceres di Interesse Nazionale 2002 (to L. R.).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.

Dagger To whom correspondence should be addressed. Tel.: 39-025033-0370; Fax: 39-025033-0365; E-mail paola.viani@unimi.it.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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