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J. Biol. Chem., Vol. 277, Issue 40, 37630-37636, October 4, 2002
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From the Departments of Obstetrics and Gynecology and Molecular and
Medical Pharmacology and Jonsson Comprehensive Cancer Center, David
Geffen School of Medicine at UCLA, Los Angeles, California
90095-1740
We have previously reported that
N
Caspase-8-mediated BID Cleavage and Release of Mitochondrial
Cytochrome c during
N
-Hydroxy-L-arginine-induced
Apoptosis in MDA-MB-468 Cells
ANTAGONISTIC EFFECTS OF L-ORNITHINE*
-hydroxy-L-arginine (NOHA), a
stable intermediate product formed during the conversion of L-arginine to nitric oxide, induced apoptosis in MDA-MB-468
cells, and this action was antagonized in the presence of
L-ornithine. We also reported that apoptosis induced
by NOHA in this cell line could not be explained on the basis of a
reduction of intracellular polyamines. In the current study, we
investigated other potential mechanism(s) by which NOHA may have
induced apoptosis in this cell line. We observed that NOHA initially
activated caspase-8 and induced cleavage of BH3 interacting
domain. This was followed by release of cytochrome c and
subsequently, activation of downstream caspases-9 and -3 to cleave
poly(ADP-ribose) polymerase. We also observed that NOHA induced a rapid
and persistent hyperpolarization of the mitochondrial membrane
potential rather than depolarization indicating that the release of
cytochrome c by NOHA was by a mechanism independent of the
mitochondrial transition pore. Exogenous L-ornithine did
not inhibit NOHA-induced caspase-8 activation and cleavage of
BH3 interacting domain but acted at the mitochondrial level and inhibited the NOHA-induced cytochrome c release and apoptosis.
*
This work was supported in part by Palomba Weingarten, the
Allegra Charach Cancer Research Fund, and United States Public Health
Service Grant CA-78357 (to G. C).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.
To whom correspondence should be addressed: Dept. of Obstetrics
and Gynecology and Molecular and Medical Pharmacology and Jonsson
Comprehensive Cancer Center, David Geffen School of Medicine at UCLA,
10833 Le Conte Ave., Los Angeles, CA 90095-1740. Tel.: 310-206-6575;
Fax: 310-206-3670; E-mail: gchaudhuri@mednet.ucla.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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