title: Derivate isocorydine inhibits cell proliferation in hepatocellular carcinoma cell lines by inducing G2/M cell cycle arrest and apoptosis.
abstract: 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.
authors.affiliation: Shanghai Medical College, Fudan University, Shanghai, China.|State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Tian
authors.affiliation: Shanghai Medical College, Fudan University, Shanghai, China.|State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Li
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Ge
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Fangyu
authors.initials: F
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Lixing
authors.initials: L
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.affiliation: Key Laboratory of Chemistry of Northwestern Plant Resources and Key Laboratory Fornatural Medicine of Gansu Province, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou, China.
authors.forename: Junxi
authors.initials: J
authors.lastname: Liu
authors.affiliation: College of Life Sciences and Chemistry, Tianshui Normal University, Tianshui, China.
authors.forename: Tingpu
authors.initials: T
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Yao
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Jiaotong University School of Medicine, Shanghai, China. jjli@shsci.org.
authors.forename: Jinjun
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001060:Aporphines / Q000494:pharmacology*; D022782:CCAAT-Enhancer-Binding Protein-beta; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D009687:Nuclear Proteins / Q000378:metabolism; D010671:Phenylurea Compounds / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays; D000097642:GADD45 Proteins
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D001060:Aporphines; D022782:CCAAT-Enhancer-Binding Protein-beta; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D009536:Niacinamide; D009687:Nuclear Proteins; D010671:Phenylurea Compounds; D000077157:Sorafenib; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C030168:isocorydine
keywords: Cell cycle; GADD45A; Hepatocellular carcinoma; d-ICD