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.

Grassilli, E., Ballabeni, A., Maellaro, E., DEL BELLO, B., & Helin, K. (2004). Loss of MYC Confers Resistance to Doxorubicin-induced Apoptosis by Preventing the Activation of Multiple Serine Protease- and Caspase-mediated Pathways. THE JOURNAL OF BIOLOGICAL CHEMISTRY, 279(20), 21318-21326 [10.1074/jbc.M313532200].

Loss of MYC Confers Resistance to Doxorubicin-induced Apoptosis by Preventing the Activation of Multiple Serine Protease- and Caspase-mediated Pathways

MAELLARO, E.;DEL BELLO, B.;
2004

Abstract

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.
Grassilli, E., Ballabeni, A., Maellaro, E., DEL BELLO, B., & Helin, K. (2004). Loss of MYC Confers Resistance to Doxorubicin-induced Apoptosis by Preventing the Activation of Multiple Serine Protease- and Caspase-mediated Pathways. THE JOURNAL OF BIOLOGICAL CHEMISTRY, 279(20), 21318-21326 [10.1074/jbc.M313532200].
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11365/7492
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