Grifolin, a potent antitumour natural product upregulates death-associated protein kinase 1 DAPK1 via p53 in nasopharyngeal carcinoma cells
Grifolin, a potent antitumour natural product upregulates death-associated protein kinase 1 DAPK1 via p53 in nasopharyngeal carcinoma cells
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Grifolin 是一种有效的抗肿瘤天然产物，可在鼻咽癌细胞中通过 p53 上调死亡相关蛋白激酶 1 DAPK1。
DOI：
10.1016/j.ejca.2010.09.021
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发表时间：
2011-01-01
影响因子：
8.4
通讯作者：
Cao, Ya
中科院分区：
文献类型：
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作者：
Luo, Xiang-jian;Li, Li-li;Cao, Ya
Grifolin是一种从蘑菇Albatrellus confluens鲜子实体中分离得到的次级代谢物，本课组前期研究表明Grifolin通过诱导细胞凋亡的方式在体外抑制某些癌细胞的生长。然而，其作用机制尚不完全清楚。凋亡相关基因表达谱分析提示，死亡相关蛋白激酶1 （dapk1）基因在grifolin治疗的鼻咽癌细胞CNE1中至少上调两倍。在此，我们进一步研究了DAPK1在grifolin诱导的细胞凋亡中的作用。我们观察到grifolin在鼻咽癌细胞CNE1中以剂量依赖的方式诱导DAPK1蛋白和mRNA水平。我们发现grifolin增加了转录因子p53蛋白的Ser392和Ser20磷酸化水平，从而促进其转录活性。此外，通过EMSA和ChIP分析证实，在grifolin的诱导下，p53对dapk1基因启动子的募集明显增强。有研究表明，将靶向DAPK1的siRNA引入CNE1细胞，可显著干扰grifolin诱导的凋亡效应以及caspase-3的激活，从而支持了DAPK1参与grifolin诱导的细胞凋亡。在人类乳腺癌和结肠癌的肿瘤细胞中也观察到Grifolin通过p53诱导DAPK1的上调。研究结果表明，通过p53-DAPK1通路上调DAPK1是grifolin诱导细胞凋亡的重要机制。由于越来越多的证据表明，在多种肿瘤类型中，DAPK1的表达显著缺失，因此grifolin可能是通过靶向DAPK1干预癌症的一个有希望的候选者。(C) 2010 Elsevier Ltd.版权所有。
Grifolin, a secondary metabolite isolated from the fresh fruiting bodies of the mushroom Albatrellus confluens, has been shown to inhibit the growth of some cancer cell lines in vitro by induction of apoptosis in previous studies of our group. However, the mechanisms of action are not completely understood. An apoptosis-related gene expression profiling analysis provided a clue that death-associated protein kinase 1 (dapk1) gene was upregulated at least twofold in response to grifolin treatment in nasopharyngeal carcinoma cell CNE1. Here, we further investigated the role of DAPK1 in apoptotic effect induced by grifolin. We observed that protein as well as mRNA level of DAPK1 was induced by grifolin in a dose-dependent manner in nasopharyngeal carcinoma cell CNE1. We found that grifolin increased both Ser392 and Ser20 phosphorylation levels of transcription factor p53 protein, which could promote its transcriptional activity. Moreover, induced by grifolin, the recruitment of p53 to dapk1 gene promoter was confirmed to enhance markedly using EMSA and ChIP assays analysis. The involvement of DAPK1 in grifolin-induced apoptosis was supported by the studies that introducing siRNA targeting DAPK1 to CNE1 cells remarkably interfered grifolin-caused apoptotic effect as well as the activation of caspase-3. Grifolin induced upregulation of DAPK1 via p53 was also observed in tumour cells derived from human breast cancer and human colon cancer. The findings suggest that upregulation of DAPK1 via p53-DAPK1 pathway is an important mechanism of grifolin contributing to its ability to induce apoptotic effect. Since growing evidence found a significant loss of DAPK1 expression in a large variety of tumour types, grifolin may represent a promising candidate in the intervention of cancer via targeting DAPK1. (C) 2010 Elsevier Ltd. All rights reserved.