Involvement of p53 in Oroxylin A-Induced Apoptosis in Cancer Cells
Involvement of p53 in Oroxylin A-Induced Apoptosis in Cancer Cells
复制标题
p53 参与 Oroxylin A 诱导的癌细胞凋亡
DOI：
10.1002/mc.20570
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发表时间：
2009-12-01
影响因子：
4.6
通讯作者：
Guo, Qinglong
中科院分区：
文献类型：
--
作者：
Mu, Rong;Qi, Qi;Guo, Qinglong
Oroxylin A是一种从黄芩中提取的天然单黄酮，根据我们之前的研究，Oroxylin A具有抗癌活性，并诱导人肝癌HepG2细胞凋亡。在本研究中，我们研究了p53是否参与oroxylin a引发的癌细胞活力抑制和凋亡诱导。在一组不同的癌细胞系中，oroxylin a在wtp53细胞中比在mtp53或p53-null细胞中观察到更有效的抑制作用。此外，转染p53- sirna的HepG2细胞显示oroxylin A诱导的凋亡水平低于转染对照sirna的细胞。同样，oroxylin A处理后，转染wtp53质粒后，p53缺失的K-562细胞凋亡率提高。Western blot和实时RT-PCR检测结果显示，oroxylin A在HepG2和过表达p53的K-562细胞中显著上调p53蛋白的表达，但对p53 mRNA的合成没有影响。此外，与环己亚胺共处理后，oroxylin A对p53表达的影响仍然很小。检测到p53、MDM2蛋白的负调控因子，并观察到表达下调。在MG132（一种蛋白酶体介导的蛋白水解抑制剂）的存在下，p53的表达没有变化。此外，抗氧化剂n -乙酰- l-半胱氨酸可以明显消除oroxylin A引发的p53稳定化作用。因此，综上所述，oroxylin A通过下调MDM2表达，干扰MDM2介导的蛋白酶体相关p53降解，在翻译后水平上稳定p53表达并诱导凋亡。这表明oroxylin A可以作为一种潜在的新型癌症治疗药物。(C) 2009 Wiley-Liss, Inc。
Oroxylin A, a naturally occurring monoflavonoid extracted from Scutellariae radix, exhibits anticancer activity and induces apoptosis in human hepatocellular carcinoma HepG2 cells according to our previous data. in this study, we investigate whether p53 is involved in oroxylin A-triggered viability inhibition and apoptosis induction in cancer cells. In a panel of different cancer cell lines, more potent inhibitory effects of oroxylin A were observed in wtp53 cells than those in mtp53 or p53-null cells. Moreover, p53-siRNA-transfected HepG2 cells showed lower levels of apoptosis induced by oroxylin A than control-siRNA-transfected cells. Likewise, after oroxylin A treatment, p53-null K-562 cells displayed promoted apoptosis rate when transfected with wtp53 plasmid. Western blot and real-time RT-PCR assay revealed that oroxylin A markedly upregulated p53 protein expression in HepG2 and p53-overexpressing K-562 cells, but had no influence on p53 mRNA synthesis. Furthermore, after co-treatment with cycloheximide, oroxylin A still exerted a little effect on p53 expression. The negative regulator of p53, MDM2 protein was detected, and downregulated expression was observed. In the presence of MG132, an inhibitor of proteasome-mediated proteolysis, no change in p53 expression was obtained. Additionally, the antioxidant N-acetyl-L-cysteine could obviously abrogate p53 stabilization triggered by oroxylin A. Therefore, it is summarized that oroxylin A stabilized p53 expression and induced apoptosis at the posttranslational level via downregulating MDM2 expression and interfering MDM2-modulated proteasome-related p53 degradation. This indicated that oroxylin A could be served as a potential, novel agent candidate for cancer therapy. (C) 2009 Wiley-Liss, Inc.