Hassan M, Alaoui A, Feyen O, Mirmohammadsadegh A, Essmann F, Tannapfel A, Gulbins E, Schulze-Osthoff K, Hengge U R
Department of Dermatology, Heinrich-Heine-University, Duesseldorf, Germany.
Oncogene. 2008 Jul 31;27(33):4557-68. doi: 10.1038/onc.2008.90. Epub 2008 Apr 14.
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.
目前，人们对黑色素瘤抗凋亡的分子机制仅了解了一部分。在本研究中，我们检测了促凋亡的仅含BH3结构域蛋白Noxa的基因转移和表达情况，将其作为化疗的替代方法，并研究了调节Noxa诱导凋亡的分子机制。Noxa基因转移导致线粒体以及首次发现的内质网功能失调，从而导致活性氧的积累。有趣的是，Noxa的表达不仅触发了经典的线粒体半胱天冬酶级联反应，还导致凋亡信号调节激酶1及其下游效应物c-Jun氨基末端激酶和p38的激活。抗氧化剂可消除这些激酶的激活。此外，通过RNA干扰或药物抑制剂抑制这些激酶可显著减弱Noxa诱导的凋亡。因此，我们的数据证明了多条途径参与了由线粒体和内质网触发的Noxa诱导的凋亡，并表明Noxa基因转移可作为化疗的补充方法。
