Proapoptotic compound ARC targets Akt and N-myc in neuroblastoma cells
Proapoptotic compound ARC targets Akt and N-myc in neuroblastoma cells
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DOI：
10.1038/sj.onc.1210692
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发表时间：
2008-01-24
期刊：
影响因子：
8
通讯作者：
Gartel, A. L.
中科院分区：
文献类型：
--
作者：
Radhakrishnan, S. K.;Halasi, M.;Gartel, A. L.
我们之前已经描述了核苷类似物转录抑制剂 ARC（4-氨基-6-肼基-7-β-D-呋喃核糖基-7H-吡咯并[2,3-d]-嘧啶-5-甲酰胺）的鉴定，该抑制剂能够诱导不同来源的癌细胞系凋亡。在这里，我们报告了一组神经母细胞瘤细胞系上 ARC 的特征。我们发现这些细胞系对 ARC 的敏感性比对众所周知的核苷类似物 DRB（5,6-二氯-1-β-呋喃糖基苯并咪唑）的敏感性高 10 倍以上，并且 ARC 诱导的细胞凋亡是通过线粒体损伤进行的。此外，我们还观察到 ARC 介导的细胞死亡伴随着 caspase-3 裂解和抗凋亡蛋白（如 Mcl-1 和生存素）的抑制。相反，我们发现 Mcl-1 的过度表达可以保护神经母细胞瘤细胞系 NB-1691 免受 ARC 诱导的细胞凋亡。此外，我们发现，虽然 ARC 抑制多种癌细胞系中 Akt Ser-473 的磷酸化，但肉豆蔻酰化 Akt 的强制表达促进了神经母细胞瘤细胞对 ARC 诱导的细胞凋亡的抵抗。此外，我们观察到 ARC 能够下调 N-myc（神经母细胞瘤中常见的扩增癌基因）的蛋白水平，而 Akt 可以保护 N-myc 免受 ARC 诱导的下调。这些数据表明ARC可能拮抗不同的抗凋亡途径并通过多种机制诱导神经母细胞瘤细胞凋亡。总体而言，ARC 可能是针对神经母细胞瘤的抗癌药物开发的一个有吸引力的候选者。
We have previously described the identification of a nucleoside analog transcriptional inhibitor ARC (4-amino- 6-hydrazino-7-beta-D-ribofuranosyl-7H-pyrrolo[ 2,3-d]- pyrimidine-5-carboxamide) that was able to induce apoptosis in cancer cell lines of different origin. Here, we report the characterization of ARC on a panel of neuroblastoma cell lines. We found that these cell lines were more than 10-fold sensitive to ARC than to the well-known nucleoside analog DRB (5,6-dichloro-1-beta-Dribofuranosylbenzimidazole), and that ARC-induced apoptosis proceeds through mitochondrial injury. Also, we observed that ARC-mediated cell death was accompanied by caspase-3 cleavage and repression of antiapoptotic proteins such as Mcl-1 and survivin. Conversely, we found that overexpression of Mcl-1-protected neuroblastoma cell line NB-1691 from ARC-induced apoptosis. Furthermore, we found that while ARC inhibited the phosphorylation of Akt Ser-473 in multiple cancer cell lines, forced expression of myristoylated Akt promoted resistance to ARC-induced apoptosis in neuroblastoma cells. In addition, we observed that ARC was able to downregulate the protein levels of N-myc, a commonly amplified oncogene in neuroblastomas, and Akt protected N-myc from ARC-induced downregulation. These data suggest that ARC may antagonize different antiapoptotic pathways and induce apoptosis in neuroblastoma cells via multiple mechanisms. Overall, ARC could represent an attractive candidate for anticancer drug development against neuroblastomas.