Derivate isocorydine inhibits cell proliferation in hepatocellular carcinoma cell lines by inducing G2/M cell cycle arrest and apoptosis
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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.
Keywordsd-ICD Cell cycle GADD45A Hepatocellular carcinoma
This work was supported in part by grants from the National Key Program for Basic Research of China (973) (2015CB553905), National Natural Science Foundation of China (81272438, 81472726, 81472570, 81372192, 31360603), Key Discipline and Specialty Foundation of Shanghai Municipal Commission of Health and Family Planning, the National KeySci-Tech Special Project of China (2013ZX10002-011), Innovation Program of Shanghai Municipal Education Commission (13ZZ082), and the SKLORG Research foundation (91-13-02, 91-14-09).
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Conflicts of interest
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