Derivate isocorydine inhibits cell proliferation in hepatocellular carcinoma cell lines by inducing G2/M cell cycle arrest and apoptosis
Derivate isocorydine inhibits cell proliferation in hepatocellular carcinoma cell lines by inducing G2/M cell cycle arrest and apoptosis
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衍生物异紫堇啶通过诱导 G2/M 细胞周期停滞和凋亡来抑制肝细胞癌细胞系的细胞增殖
DOI：
10.1007/s13277-015-4362-6
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发表时间：
2016-05-01
期刊：
影响因子：
--
通讯作者：
Li, Jinjun
中科院分区：
文献类型：
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作者：
Chen, Lijuan;Tian, Hua;Li, Jinjun
我们先前已经证明异肾上腺素(ICD)可以作为一种潜在的抗肝细胞癌药物。一种新的异鸟苷衍生物(d-ICD)可以显著提高其在肿瘤中的抗癌活性。然而，d-ICD对肝癌细胞作用的分子机制尚不清楚。在本研究中，我们观察到d-ICD以浓度依赖的方式抑制细胞增殖和诱导肝癌细胞凋亡。我们在体内外发现d-ICD通过DNA损伤45α(GADD45A)和p21途径诱导肝癌细胞G2/M期停滞。在d-ICD处理的细胞中，细胞周期相关蛋白Cyclin B1和p-CDC2上调，而p-Cyclin B1、CDC2和E2F1受到抑制。在d-ICD处理的肝癌细胞中，GADD45A基因的敲除可以逆转p21的表达。CCAAT/增强子结合蛋白β(C/EBPβ)联合d-ICD的增强表达增强了p21在肝癌细胞中的表达。荧光素酶报告实验表明，C/eBPβ通过提高GADD45A启动子的活性来上调GADD45A的表达。提示d-ICD通过激活C/EBPGADD45A-p21途径抑制肝癌细胞增殖，诱导细胞周期停滞。D-ICD有望成为治疗肝癌的一种有前途的化疗药物。
We have previously demonstrated that isocorydine (ICD) can be served as a potential antitumor agent in hepatocellular carcinoma (HCC). A novel derivate of isocorydine (d-ICD) could significantly improve its anticancer activity in tumors. However, the molecular mechanisms of d-ICD on HCC cells remain to be unclear. In this study, we observed that d-ICD inhibited cell proliferation and induced apoptosis of HCC cells in a concentration-dependent manner. We found d-ICD induced G2/M cycle arrest of HCC cells via DNA damage 45 alpha (GADD45A) and p21 pathway in vitro and in vivo. In d-ICD-treated cells, cell cycle-related proteins cyclin B1 and p-CDC2 were upregulated and p-cyclin B1, CDC2, and E2F1 were inhibited. p21 expression can be reversed by knockdown of GADD45A in d-ICD-treated HCC cells. Enforced expression of CCAAT/enhancer-binding protein β (C/EBPβ) in combination with d-ICD enhanced the p21 expression in HCC cells. Furthermore, the luciferase reporter assay showed that upregulation of GADD45A by C/EBPβ was achieved through the increase of GADD45A promoter activity. These findings indicate that d-ICD inhibits cell proliferation and induces cell cycle arrest through activation of C/EBPβ-GADD45A-p21 pathway in HCC cells. d-ICD might be a promising chemotherapeutic agent for the treatment of HCC.