DAPK1 mediates the G1 phase arrest in human nasopharyngeal carcinoma cells induced by grifolin, a potential antitumor natural product
DAPK1 mediates the G1 phase arrest in human nasopharyngeal carcinoma cells induced by grifolin, a potential antitumor natural product
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DAPK1 介导 Grifolin（一种潜在的抗肿瘤天然产物）诱导的人鼻咽癌细胞 G1 期阻滞。
DOI：
10.1016/j.ejphar.2011.08.026
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发表时间：
2011-11-30
影响因子：
5
通讯作者：
Cao, Ya
中科院分区：
文献类型：
--
作者：
Luo, Xiang-jian;Li, Wei;Cao, Ya
Grifolin是从Albatrellus confluens新鲜子实体中分离的次级代谢产物，在我们小组的先前研究中已显示出诱导肿瘤细胞的Cl期细胞周期停滞。然而，其作用机制尚未完全了解。我们的研究小组进一步证实，在鼻咽癌细胞（NPC）中，grifolin上调死亡相关蛋白激酶1（DAPK 1）。在这里，我们发现，在鼻咽癌细胞CNE 1中，grifolin诱导DAPK 1（Ser 308）去磷酸化以激活DAPK 1，随后磷酸化其潜在的下游效应子p21（Thr 145）。通过引入靶向DAPK 1的siRNA抑制DAPK 1逆转了grifolin诱导的p21磷酸化。此外，我们证实了grifolin增加了p21的半衰期，并促进了其稳定性。流式细胞仪分析表明DAPK 1参与了grifolin诱导的CNE 1细胞Cl期阻滞。在另一株鼻咽癌细胞HONE 1中，证实了grifolin诱导的类似效应及其机制。另外，我们观察到grifolin促进DAPK 1和ERK 1/2的蛋白质-蛋白质相互作用，从而阻止ERK 1/2的核仁易位。我们的研究结果表明，DAPK 1起着至关重要的作用，诱导细胞周期停滞在Cl期的grifolin。Grifolin通过靶向DAPK 1信号通路诱导细胞周期C1期阻滞，可能成为预防和干预癌症的一个有前途的候选药物。(C)2011 Elsevier B. V.保留所有权利。
Grifolin, a secondary metabolite isolated from the fresh fruiting bodies of the mushroom Albatrellus confluens, has been shown to induce Cl phase cell-cycle arrest in tumor cells in previous studies of our group. However, the mechanisms of action are not completely understood. Our group further demonstrated that grifolin upregulates death-associated protein kinase 1 (DAPK1) in nasopharyngeal carcinoma cells (NPCs). Here, we found that grifolin induced dephosphorylation of DAPK1 (Ser308) to activate DAPK1 and subsequent phosphorylation of its potential downstream effector p21 (Thr145) in nasopharyngeal carcinoma cell CNE1. Inhibition of DAPK1 by introducing siRNA targeting DAPK1 reversed the grifolin- induced phosphorylation of p21. Furthermore, we confirmed that grifolin increased the half-life of p21 and promoted its stability. Flow cytometry analysis demonstrated that DAPK1 was involved in grifolin-induced Cl phase arrest in CNE1 cells. The similar effects induced by grifolin and mechanism beneath were identified in another nasopharyngeal carcinoma cell HONE1. In addition, we observed that grifolin promoted the protein-protein interaction of DAPK1 and ERK1/2 to prevent ERK1/2 nucleolus translocation. Our findings indicate that DAPK1 plays a crucial role in the induction of cell-cycle arrest at Cl phase by grifolin. Grifolin might represent a promising candidate in the prevention and intervention of cancer by targeting DAPK1 signaling to induce cell cycle Cl phase arrest. (C) 2011 Elsevier B.V. All rights reserved.