title: Romidepsin induces G2/M phase arrest via Erk/cdc25C/cdc2/cyclinB pathway and apoptosis induction through JNK/c-Jun/caspase3 pathway in hepatocellular carcinoma cells.
abstract: The aim of the study is to demonstrate the effect of Romidepsin in hepatocellular carcinoma (HCC) by inducing G2/M phase arrest via Erk/cdc25C/cdc2/cyclinB pathway and apoptosis through JNK/c-Jun/caspase3 pathway in vitro and in vivo. Human HCC cell lines were cultured with Romidepsin and DMSO (negative control) and 5-fluorouracil (positive control). Then the cells' viability and apoptosis were determined by cell proliferation assay and flow cytometry. Protein concentrations and expression changes were measured by Western blot. Subsequently, Huh7 cells were subcutaneously inoculated into the nude mice, which were employed to further probe the tumor-suppressive effect of Romidepsin in vivo. Romidepsin treatment led to a time- and dose-dependent induction of cell cycle arrest in the G2/M phase and apoptosis. G2/M phase arrest inhibited the proliferation of HCC cells by alterations in p21/cdc25C/cdc2/cyclinB proteins. Increased concentrations of Erk and JNK phosphorylations were observed in a dose-dependent manner in the Romidepsin group, but p38 phosphorylation was not affected. G2/M phase arrest and the apoptosis of HCC cells induced by Romidepsin were mediated by the activation of Erk/MAPK pathways and JNK/MAPK pathways. The tumor size was significantly larger in the negative control group compared to Romidepsin group and no significant loss in body weight was observed in the Romidepsin group. Our findings offer proof-of-concept for use of Romidepsin as a novel class of chemotherapy in the treatment of HCC.
authors.affiliation: Department of Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China; Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Wei-Jian
authors.initials: WJ
authors.lastname: Sun
authors.affiliation: Department of Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
authors.forename: He
authors.initials: H
authors.lastname: Huang
authors.affiliation: Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Zhejiang University, Hangzhou, China.
authors.forename: Bin
authors.initials: B
authors.lastname: He
authors.affiliation: Department of Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
authors.forename: Dan-Hong
authors.initials: DH
authors.lastname: Hu
authors.affiliation: Department of Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
authors.forename: Pi-Hong
authors.initials: PH
authors.lastname: Li
authors.affiliation: Department of Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
authors.forename: Yao-Jun
authors.initials: YJ
authors.lastname: Yu
authors.affiliation: Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Xiao-Hu
authors.initials: XH
authors.lastname: Zhou
authors.affiliation: Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Lv
authors.affiliation: Department of Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
authors.forename: Tian-Ye
authors.initials: TY
authors.lastname: Hu
authors.affiliation: Department of Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
authors.forename: Zhi-Chao
authors.initials: ZC
authors.lastname: Yao
authors.affiliation: Department of Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China. Electronic address: lumingdong126@126.com.
authors.forename: Ming-Dong
authors.initials: MD
authors.lastname: Lu
authors.affiliation: Department of Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China. Electronic address: 13968888872@163.com.
authors.forename: Xian
authors.initials: X
authors.lastname: Shen
authors.affiliation: Department of Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China. Electronic address: zzq6529921@126.com.
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Zheng
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D016203:CDC2 Protein Kinase; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019926:Cyclin B / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D047630:Depsipeptides / Q000494:pharmacology* / Q000627:therapeutic use; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D064593:Heterografts; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D015398:Signal Transduction; D020687:cdc25 Phosphatases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D019926:Cyclin B; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; C087123:romidepsin; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; C517009:CDC25C protein, human; D020687:cdc25 Phosphatases; D053148:Caspase 3
keywords: 5-Fluorouracil (PubChem CID: 3385); Caspase3 pathway; Cdc2; DAPI (PubChem CID: 2954); DMSO (PubChem CID: 679); Erk; Ethanol (PubChem CID: 702); Formaldehyde solution (PubChem CID: 712); G2; Glycine (PubChem CID: 750); Hepatocellular carcinoma; JNK; M phase arrest; Methanol (PubChem CID: 887); Paraformaldehyde (PubChem CID: 123127); Romidepsin; Romidepsin (PubChem CID: 5352062); SB203580 (PubChem CID: 176155); SCH772984 (PubChem CID: 24866313); SP600125 (PubChem CID: 8515); Tween 20 (PubChem CID: 443314); Z-VAD-FMK (PubChem CID: 5497174); c-Jun; cdc25C; cyclinB pathway