The BH3-only member Noxa causes apoptosis in melanoma cells by multiple pathways
The BH3-only member Noxa causes apoptosis in melanoma cells by multiple pathways
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DOI：
10.1038/onc.2008.90
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发表时间：
2008-07-31
期刊：
影响因子：
8
通讯作者：
Hengge, U. R.
中科院分区：
文献类型：
--
作者：
Hassan, M.;Alaoui, A.;Hengge, U. R.
黑色素瘤抵抗细胞凋亡的分子原因目前只有部分了解。在本研究中，我们检测了促凋亡的BH3-Only蛋白NOXA作为化疗的替代方法的基因转移和表达，并探讨了调控NOXA诱导细胞凋亡的分子机制。NOXA基因转移导致线粒体和内质网的调节失调，导致活性氧积累。有趣的是，Noxa的表达不仅触发了经典的线粒体caspase级联反应，还导致了凋亡信号调节激酶1及其下游效应因子c-jun氨基末端激酶和p38的激活。这些激酶的激活被抗氧化剂消除。此外，用RNA干扰或药物抑制剂抑制这些激酶可显著减弱诺沙星诱导的细胞凋亡。因此，我们的数据提供了证据，证明在线粒体和内质网触发的NOXA诱导的细胞凋亡中有多条途径参与，并提示NOXA基因转移是一种补充化疗方法。
The molecular causes for resistance of melanoma to apoptosis are currently only partly understood. In the present study, we examined gene transfer and expression of the proapoptotic BH3-only protein Noxa as an alternative approach to chemotherapy and investigated the molecular mechanisms regulating Noxa-induced apoptosis. Noxa gene transfer caused dysregulation of both mitochondria and, as shown for the first time, also the endoplasmic reticulum, resulting in the accumulation of reactive oxygen species. Interestingly, expression of Noxa not only triggered the classical mitochondrial caspase cascade, but also resulted in the activation of apoptosis signal-regulating kinase1 and its downstream effectors c-Jun N-terminal kinase and p38. The activation of these kinases was abolished by antioxidants. Moreover, inhibition of the kinases by RNA interference or pharmacological inhibitors significantly attenuated Noxa-induced apoptosis. Thus, our data provide evidence for the involvement of multiple pathways in Noxa-induced apoptosis that are triggered at mitochondria and the endoplasmic reticulum, and suggest Noxa gene transfer as a complementary approach to chemotherapy.