Apoptosis induced by proteasome inhibition in cancer cells:: predominant role of the p53/PUMA pathway
Apoptosis induced by proteasome inhibition in cancer cells:: predominant role of the p53/PUMA pathway
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DOI：
10.1038/sj.onc.1209974
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发表时间：
2007-03-01
期刊：
影响因子：
8
通讯作者：
Prehn, J. H. M.
中科院分区：
文献类型：
--
作者：
Concannon, C. G.;Koehler, B. F.;Prehn, J. H. M.
蛋白酶体已成为血液恶性肿瘤和实体瘤（包括中枢神经系统肿瘤）的新靶点。为了鉴定癌细胞中蛋白酶体系统抑制后激活的细胞死亡途径，我们用选择性蛋白酶体抑制剂（PI）环氧霉素（Epoxo）处理人SH-SY 5 Y神经母细胞瘤细胞。长时间暴露于Epoxo与多聚泛素化蛋白和p53水平升高、线粒体释放细胞色素c以及半胱天冬酶激活相关。使用高密度寡核苷酸微阵列分析全局基因表达显示，Epoxo触发了两个Bcl-2同源结构域-3-only（BH 3-only）基因p53上调凋亡调节因子（p53）和Bim的转录激活。随后的研究表明，Epoxo诱导的胱天蛋白酶激活和细胞凋亡主要依赖于Bim-和Bim-缺陷细胞。在HCT 116人结肠癌细胞中对Epoxo的转录反应的进一步表征表明，p53或p53 A的缺陷显着保护HCT 116细胞免受Epoxo诱导的细胞凋亡，p53或p53 A的诱导是依赖性的。我们的数据表明，p53的激活和其靶基因的转录诱导p53蛋白酶体抑制剂诱导的细胞凋亡的癌细胞的敏感性中发挥了重要作用，并暗示与PI的抗肿瘤治疗可能是特别有用的癌症与功能p53。
The proteasome has emerged as a novel target for antineoplastic treatment of hematological malignancies and solid tumors, including those of the central nervous system. To identify cell death pathways activated in response to inhibition of the proteasome system in cancer cells, we treated human SH-SY5Y neuroblastoma cells with the selective proteasome inhibitor (PI) epoxomicin (Epoxo). Prolonged exposure to Epoxo was associated with increased levels of poly-ubiquitinylated proteins and p53, release of cytochrome c from the mitochondria, and activation of caspases. Analysis of global gene expression using high-density oligonucleotide microarrays revealed that Epoxo triggered transcriptional activation of the two Bcl-2-homology domain-3-only (BH3-only) genes p53 upregulated modulator of apoptosis (PUMA) and Bim. Subsequent studies in PUMA- and Bim-deficient cells indicated that Epoxo-induced caspase activation and apoptosis was predominantly PUMA- dependent. Further characterization of the transcriptional response to Epoxo in HCT116 human colon cancer cells demonstrated that PUMA induction was p53-dependent; with deficiency in either p53 or PUMA significantly protected HCT116 cells against Epoxo-induced apoptosis. Our data suggest that p53 activation and the transcriptional induction of its target gene PUMA play an important role in the sensitivity of cancer cells to apoptosis induced by proteasome inhibition, and imply that antineoplastic therapies with PIs might be especially useful in cancers with functional p53.