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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.
Biochem Pharmacol. 2017 03 01; 127:90-100.BP

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+Show Affiliations

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.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; Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Zhejiang University, Hangzhou, China.Department of Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.Department of Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.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.Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.Department of Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.Department of Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.Department of Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.Department of Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China. Electronic address: lumingdong126@126.com.Department of Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China. Electronic address: 13968888872@163.com.Department of Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China. Electronic address: zzq6529921@126.com.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28012958

Citation

Sun, Wei-Jian, et al. "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." Biochemical Pharmacology, vol. 127, 2017, pp. 90-100.
Sun WJ, Huang H, He B, et al. 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. Biochem Pharmacol. 2017;127:90-100.
Sun, W. J., Huang, H., He, B., Hu, D. H., Li, P. H., Yu, Y. J., Zhou, X. H., Lv, Z., Zhou, L., Hu, T. Y., Yao, Z. C., Lu, M. D., Shen, X., & Zheng, Z. Q. (2017). 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. Biochemical Pharmacology, 127, 90-100. https://doi.org/10.1016/j.bcp.2016.12.008
Sun WJ, et al. 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. Biochem Pharmacol. 2017 03 1;127:90-100. PubMed PMID: 28012958.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Sun,Wei-Jian, AU - Huang,He, AU - He,Bin, AU - Hu,Dan-Hong, AU - Li,Pi-Hong, AU - Yu,Yao-Jun, AU - Zhou,Xiao-Hu, AU - Lv,Zhen, AU - Zhou,Lei, AU - Hu,Tian-Ye, AU - Yao,Zhi-Chao, AU - Lu,Ming-Dong, AU - Shen,Xian, AU - Zheng,Zhi-Qiang, Y1 - 2016/12/22/ PY - 2016/12/12/received PY - 2016/12/13/accepted PY - 2016/12/26/pubmed PY - 2017/4/28/medline PY - 2016/12/26/entrez KW - 5-Fluorouracil (PubChem CID: 3385) KW - Caspase3 pathway KW - Cdc2 KW - DAPI (PubChem CID: 2954) KW - DMSO (PubChem CID: 679) KW - Erk KW - Ethanol (PubChem CID: 702) KW - Formaldehyde solution (PubChem CID: 712) KW - G2 KW - Glycine (PubChem CID: 750) KW - Hepatocellular carcinoma KW - JNK KW - M phase arrest KW - Methanol (PubChem CID: 887) KW - Paraformaldehyde (PubChem CID: 123127) KW - Romidepsin KW - Romidepsin (PubChem CID: 5352062) KW - SB203580 (PubChem CID: 176155) KW - SCH772984 (PubChem CID: 24866313) KW - SP600125 (PubChem CID: 8515) KW - Tween 20 (PubChem CID: 443314) KW - Z-VAD-FMK (PubChem CID: 5497174) KW - c-Jun KW - cdc25C KW - cyclinB pathway SP - 90 EP - 100 JF - Biochemical pharmacology JO - Biochem. Pharmacol. VL - 127 N2 - 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. SN - 1873-2968 UR - https://www.unboundmedicine.com/medline/citation/28012958/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_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-2952(16)30488-9 DB - PRIME DP - Unbound Medicine ER -