Abstract
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Journal of Biological Chemistry |
| Vol/bind | 279 |
| Udgave nummer | 20 |
| Sider (fra-til) | 21318-26 |
| Antal sider | 8 |
| ISSN | 0021-9258 |
| DOI | |
| Status | Udgivet - 2004 |
Bibliografisk note
Keywords: Animals; Antineoplastic Agents; Apoptosis; Caspase 3; Caspases; Cell Division; Cell Line; Doxorubicin; Enzyme Activation; Genes, myc; Rats; Serine EndopeptidasesAdgang til dokumentet
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I: Journal of Biological Chemistry, Bind 279, Nr. 20, 2004, s. 21318-26.
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review
}
TY - JOUR
T1 - Loss of MYC confers resistance to doxorubicin-induced apoptosis by preventing the activation of multiple serine protease- and caspase-mediated pathways.
AU - Grassilli, Emanuela
AU - Ballabeni, Andrea
AU - Maellaro, Emilia
AU - Del Bello, Barbara
AU - Helin, Kristian
N1 - Keywords: Animals; Antineoplastic Agents; Apoptosis; Caspase 3; Caspases; Cell Division; Cell Line; Doxorubicin; Enzyme Activation; Genes, myc; Rats; Serine Endopeptidases
PY - 2004
Y1 - 2004
N2 - c-Myc plays an essential role in proliferation, differentiation, and apoptosis. Because of its relevance to cancer, most studies have focused on the cellular consequences of c-Myc overexpression. Here, we address the role of physiological levels of c-Myc in drug-induced apoptosis. By using c-MYC null cells we confirm and extend recent reports showing a c-Myc requirement for the induction of apoptosis by a number of anticancer agents. In particular, we show that c-Myc is required for the induction of apoptosis by doxorubicin and etoposide, whereas it is not required for camptothecin-induced cell death. We have investigated the molecular mechanisms involved in executing doxorubicin-induced apoptosis and show caspase-3 activation by both mitochondria-dependent and -independent pathways. Moreover, serine proteases participate in doxorubicin-induced apoptosis partly by contributing to caspase-3 activation. Finally, a complete rescue from doxorubicin-induced apoptosis is obtained only when serine proteases, caspase-3, and mitochondrial activation are inhibited simultaneously. Interestingly, doxorubicin requires c-Myc for the activation of all of these pathways. Our findings therefore support a model in which doxorubicin simultaneously triggers multiple c-Myc-dependent apoptosis pathways.
AB - c-Myc plays an essential role in proliferation, differentiation, and apoptosis. Because of its relevance to cancer, most studies have focused on the cellular consequences of c-Myc overexpression. Here, we address the role of physiological levels of c-Myc in drug-induced apoptosis. By using c-MYC null cells we confirm and extend recent reports showing a c-Myc requirement for the induction of apoptosis by a number of anticancer agents. In particular, we show that c-Myc is required for the induction of apoptosis by doxorubicin and etoposide, whereas it is not required for camptothecin-induced cell death. We have investigated the molecular mechanisms involved in executing doxorubicin-induced apoptosis and show caspase-3 activation by both mitochondria-dependent and -independent pathways. Moreover, serine proteases participate in doxorubicin-induced apoptosis partly by contributing to caspase-3 activation. Finally, a complete rescue from doxorubicin-induced apoptosis is obtained only when serine proteases, caspase-3, and mitochondrial activation are inhibited simultaneously. Interestingly, doxorubicin requires c-Myc for the activation of all of these pathways. Our findings therefore support a model in which doxorubicin simultaneously triggers multiple c-Myc-dependent apoptosis pathways.
U2 - 10.1074/jbc.M313532200
DO - 10.1074/jbc.M313532200
M3 - Journal article
C2 - 14990581
SN - 0021-9258
VL - 279
SP - 21318
EP - 21326
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 20
ER -