Berberine induces p53-dependent cell cycle arrest and apoptosis of human osteosarcoma cells by inflicting DNA damage
Berberine induces p53-dependent cell cycle arrest and apoptosis of human osteosarcoma cells by inflicting DNA damage
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小檗碱通过造成 DNA 损伤诱导 p53 依赖性细胞周期停滞和人骨肉瘤细胞凋亡
DOI：
10.1016/j.mrfmmm.2008.12.009
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发表时间：
2009-03-09
影响因子：
2.3
通讯作者：
Shao, Changshun
中科院分区：
文献类型：
--
作者：
Liu, Zhaojian;Liu, Qiao;Shao, Changshun
生物碱黄连素被广泛用于治疗腹泻等疾病。许多实验室研究表明，它对培养的多种癌细胞具有抗增殖活性。在这份报告中，我们研究了黄连素对人骨肉瘤细胞和正常成骨细胞抑制作用的机制。抑制作用主要归因于细胞周期停滞于G1和G2/M期，其次为细胞凋亡。G1期停滞依赖于P53，因为在P53缺失的骨肉瘤细胞中，G1期停滞被取消。在诱导G1期停滞和细胞凋亡的同时，P53依赖的p21和促凋亡基因表达上调。然而，无论P53处于何种状态，黄连素均可诱导细胞发生G2/M期阻滞。有趣的是，通过H_2AX的磷酸化检测，DNA双链断裂在黄连素处理的细胞中以剂量依赖的方式显著积累。因此，黄连素发挥生长抑制作用的一个主要机制是对细胞造成基因组损伤，进而触发P53的激活和依赖于P53的细胞反应，包括细胞周期停滞和细胞凋亡。(C)2008爱思唯尔B.V.保留所有权利。
Alkaloid berberine is widely used for the treatment of diarrhea and other diseases. Many laboratory studies showed that it exhibits anti-proliferative activity against a wide spectrum of cancer cells in culture. In this report we studied the mechanisms underlying the inhibitory effects of berberine on human osteosarcoma cells and on normal osteoblasts. The inhibition was largely attributed to cell cycle arrest at G1 and G2/M, and to a less extent, to apoptosis. The G1 arrest was dependent on p53, as G1 arrest was abolished in p53-deficient osteosarcoma cells. The induction of G1 arrest and apoptosis was accompanied by a p53-dependent up-regulation of p21 and pro-apoptotic genes. However, the G2/M arrest could be induced by berberine regardless of the status of p53. Interestingly, DNA double-strand breaks, as measured by the phosphorylation of H2AX, were remarkably accumulated in berberine-treated cells in a dose-dependent manner. Thus, one major mechanism by which berberine exerts its growth-inhibitory effect is to inflict genomic lesions on cells, which in turn trigger the activation of p53 and the p53-dependent cellular responses including cell cycle arrest and apoptosis. (C) 2008 Elsevier B.V. All rights reserved.