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J. Biol. Chem., Vol. 277, Issue 51, 49531-49537, December 20, 2002
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From the Stress stimuli can mediate apoptosis by
generation of the lipid second messenger, ceramide. Herein we
investigate the molecular mechanism of ceramide signaling in
endothelial apoptosis induced by fenretinide
(N-(4-hydroxyphenyl)retinamide (4-HPR)). 4-HPR, a synthetic
derivative of retinoic acid that induces ceramide in tumor cell lines,
has been shown to have antiangiogenic effects, but the molecular
mechanism of these is largely unknown. We report that 4-HPR was
cytotoxic to endothelial cells (50% cytotoxicity at 2.4 µM, 90% at 5.36 µM) and induced a
caspase-dependent endothelial apoptosis. 4-HPR (5 µM) increased ceramide levels in endothelial cells
5.3-fold, and the increase in ceramide was required to achieve the
apoptotic effect of 4-HPR. The 4-HPR-induced increase in ceramide was
suppressed by inhibitors of ceramide synthesis, fumonisin B1, myriocin, and L-cycloserine, and 4-HPR
transiently activated serine palmitoyltransferase, demonstrating that
4-HPR induced de novo ceramide synthesis. Sphingomyelin
levels were not altered by 4-HPR, and desipramine had no effect on
ceramide level, suggesting that sphingomyelinase did not contribute to
the 4-HPR-induced ceramide increase. Finally, the pancaspase inhibitor,
t-butyloxycarbonyl-aspartyl[O-methyl]-fluoromethyl ketone, suppressed 4-HPR-mediated apoptosis but not ceramide
accumulation, suggesting that ceramide is upstream of caspases. Our
results provide the first evidence that increased ceramide biosynthesis is required for 4-HPR-induced endothelial apoptosis and present a molecular mechanism for its antiangiogenic effects.
Ceramide Signaling in Fenretinide-induced Endothelial Cell
Apoptosis*
§,,,
,,,, and
Division of Hematology-Oncology,
Childrens Hospital Los Angeles, Department of Pediatrics and the
Department of Preventive Medicine, Keck
School of Medicine, University of Southern California, Los Angeles,
California 90027, the ¶ John Wayne Cancer Institute at Saint
John's Health Center, Santa Monica, California 90404, the
Section of Hematology/Oncology, Department of Pediatrics, Herman
B Wells Center for Pediatric Research, Indiana University School of
Medicine, Indianapolis, Indiana 46202, and the
** Division of Infectious Diseases, Department of
Pediatrics, Johns Hopkins School of Medicine,
Baltimore, Maryland 21205
*
This work was supported by National Institutes of Health
Grant CA 81403, the Michael Hoefflin Children's Cancer Research Fund, and the My Brother Joey Foundation. It was also supported in part by
the Neil Bogart Memorial Fund of the T. J. Martell Foundation for
Leukemia, Cancer, and AIDS Research.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 © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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