NCPMF-60 induces G2/M cell cycle arrest and apoptosis in human hepatocellular carcinoma HepG2 cells
NCPMF-60 induces G2/M cell cycle arrest and apoptosis in human hepatocellular carcinoma HepG2 cells
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DOI：
10.1097/cad.0b013e3283405801
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发表时间：
2011-01-01
影响因子：
2.3
通讯作者：
Guo, Qing-Long
中科院分区：
文献类型：
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作者：
Dai, Qin-Sheng;Liu, Wei;Guo, Qing-Long
我们最近确定，NCPMF-60，一种新合成的黄酮类化合物，是一种活性细胞毒性成分。NCPMF-60发挥其细胞毒活性的分子机制目前尚不清楚。在这项研究中，我们表明，NCPMF-60诱导人肝癌HepG 2细胞G2/M期阻滞和凋亡。在用NCPMF-60处理HepG 2细胞后，细胞周期相关蛋白，如cyclin B1、cyclin H、CDK 7和p-CDK 1（Thr 161）下调，而p21（WAF 1/Cip 1）和p-CDK 1（Thr 14/Tyr 15）上调。NCPMF-60还抑制CDK 1/cyclinB复合物的活性。此外，我们观察到聚（ADP-核糖）聚合酶切割和激活caspase 3和caspase 9。Bax/Bcl-2的表达比例增加，其中Bax表达上调。我们还发现，在NCPMF-60处理后，p53的表达及其在Ser 15处的磷酸化积累。此外，在NCPMF-60处理的细胞中，观察到p53上调的凋亡调节剂p21（WAF 1/Cip 1）和Bax（三种p53靶基因产物）的上调，以及Bcl-2和MDM 2的下调。然而，p53并不是NCPMF-60在p21转录水平和转录后水平刺激细胞的唯一调节因子。这些结果表明，NCPMF-60确实激活了p53通路，这可能有助于其诱导HepG 2细胞的细胞周期阻滞和凋亡。总之，我们的研究结果表明，NCPMF-60诱导的细胞周期阻滞和凋亡与HepG 2细胞中p53通路的激活和CDK激活激酶活性的抑制有关。抗癌药物22：46-57（C）2011年沃尔特斯·克鲁沃健康垂直酒吧利平科特威廉姆斯&威尔金斯。
We recently established that NCPMF-60, a newly synthesized flavonoid, is an active cytotoxic component. The molecular mechanisms by which NCPMF-60 exerts its cytotoxic activity are currently unknown. In this study, we show that NCPMF-60 induces G2/M phase arrest and apoptosis in human hepatocellular carcinoma HepG2 cells. After treatment of HepG2 cells with NCPMF-60, cell cycle-related proteins, such as cyclin B1, cyclin H, CDK7, and p-CDK1 (Thr161), were downregulated, whereas p21(WAF1/Cip1) and p-CDK1 (Thr14/Tyr15) were upregulated. The activity of CDK1/cyclinB complex was also inhibited by NCPMF-60. In addition, we observed poly(ADP-ribose) polymerase cleavage and activation of caspase 3 and caspase 9. The expression ratio of Bax/Bcl-2 was increased in the treated cells, in which Bax was also upregulated. We also found that the expression of p53 and its phosphorylation at Ser15 accumulated after the treatment of NCPMF-60. Moreover, upregulation of p21(WAF1/Cip1), p53-upregulated modifier of apoptosis, and Bax, three p53-target gene products, and the downregulation of Bcl-2 and MDM2, were observed in NCPMF-60-treated cells. However, p53 is not the only regulator in the stimulation of NCPMF-60 on p21 transcriptional level and posttranscriptional level. These results suggested that NCPMF-60 indeed activated the p53 pathway, which may contribute to its induction of cell cycle arrest and apoptosis in HepG2 cells. Collectively, our findings show that cell cycle arrest and apoptosis induced by NCPMF-60 was associated with the activation of p53 pathway and the inhibition of CDK-activating kinase activity in HepG2 cells. Anti-Cancer Drugs 22:46-57 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.