Loss of MYC confers resistance to doxorubicin-induced apoptosis by preventing the activation of multiple serine protease- and caspase-mediated pathways
Loss of MYC confers resistance to doxorubicin-induced apoptosis by preventing the activation of multiple serine protease- and caspase-mediated pathways
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DOI：
10.1074/jbc.m313532200
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发表时间：
2004-05-14
影响因子：
4.8
通讯作者：
Helin, K
中科院分区：
文献类型：
--
作者：
Grassilli, E;Ballabeni, A;Helin, K
c-Myc在增殖、分化和凋亡中起重要作用。由于其与癌症的相关性，大多数研究都集中在c-Myc过表达的细胞后果上。在这里，我们解决的作用，生理水平的c-Myc在药物诱导的细胞凋亡。通过使用c-MYC空细胞，我们证实并扩展了最近的报告，显示了c-Myc的要求诱导细胞凋亡的抗癌药物。特别是，我们表明，c-Myc是所需的诱导细胞凋亡的阿霉素和依托泊苷，而喜树碱诱导的细胞死亡是不需要的。我们已经研究了参与执行阿霉素诱导的细胞凋亡的分子机制，并显示caspase-3激活的两个依赖性和非依赖性途径。此外，丝氨酸蛋白酶参与阿霉素诱导的细胞凋亡，部分通过促进caspase-3的激活。最后，只有当丝氨酸蛋白酶，半胱天冬酶-3和线粒体活化同时被抑制时，才能从阿霉素诱导的细胞凋亡中获得完全的拯救。有趣的是，阿霉素需要c-Myc来激活所有这些途径。因此，我们的研究结果支持多柔比星同时触发多个c-Myc依赖性凋亡途径的模型。
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.