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J. Biol. Chem., Vol. 277, Issue 46, 43763-43770, November 15, 2002
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From the The objective of this article is to dissect the
mechanisms by which the down-regulation of c-Myc induces programmed
cell death in melanoma cells. In stable and doxycycline-inducible M14
melanoma cells, down-regulation of c-Myc induced apoptosis subsequent
to a decrease in the intracellular reduced glutathione content and a
concomitant accumulation of its oxidized form. This redox alteration was associated with a decrease of the enzyme activities of
Glutathione Influences c-Myc-induced Apoptosis in M14 Human
Melanoma Cells*
§,¶,
,¶,,, and
Experimental Chemotherapy Laboratory, Regina
Elena Cancer Institute, Via delle Messi d'Oro, 00158 Rome, the
Department of Biology, "Tor Vergata" University, Via della
Ricerca Scientifica 00133 Rome, the
Department of Biomedical Sciences, "G.
D'Annunzio" University, Via dei Vestini, 66013 Chieti, and the
** Department of Oncology, "Mario Negri" Research
Institute, via Eritrea, 20154 Milan, Italy
-glutamyl-cysteine synthetase and NADPH-dependent GSSG
reductase, as well as a consequent glutathione release in the
extracellular medium. Cytochrome c was released into the
cytosol at very early stages of apoptosis induction, long before
detectable production of reactive oxygen species and activation of
caspase-9 and -3. Macroarray analysis revealed that down-regulation of
c-Myc produced striking changes in gene expression in the section
related to metabolism, where the expression of -glutamyl-cysteine
synthetase and GSSG reductase was found to be significantly reduced.
The addition of N-acetyl-L-cysteine or
glutathione ethyl ester inhibited the apoptotic process, thus confirming the key role of glutathione in programmed cell death induced
by c-Myc.
*
Supported by grants from the Italian Association for Cancer
Research (AIRC), Ministero della Sanità, and Consiglio
Nazionale delle Ricerche-Ministero dell'Istruzione,
dell'Università e della Ricerca.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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