title: Phosphorylation of cofilin-1 by ERK confers HDAC inhibitor resistance in hepatocellular carcinoma cells via decreased ROS-mediated mitochondria injury.
abstract: Hepatocellular carcinoma (HCC) is the most common type of liver cancer. Despite the availability of several treatment strategies, resistance to chemotherapeutic agents, which limits the effectiveness of anticancer drugs, is a major problem in cancer therapy. In this study, we used a histone deacetylases inhibitor (HDACi) to establish drug-resistant HCC cells and further analyzed the molecular mechanisms underlying the development of resistance in HCC cells. Compared with the parental cells, HDACi-resistant cells showed high metastatic and pro-survival abilities. Two-dimensional electrophoresis data showed that the cofilin-1 (CFL-1) protein was altered in HDACi-resistant cells and was highly expressed in resistant cells compared with parental cells. The molecular function of CFL-1 is actin depolymerization, and it is involved in tumor metastasis. In this study, we showed that CFL-1 inhibition decreased cell migration and increased cell apoptosis in HDACi-resistant cells. We observed that HDACi induced ROS accumulation in cells and apoptosis via promotion of the CFL-1 interaction with Bax and CFL-1 translocation to the mitochondria, resulting in cytochrome C release. Importantly, phosphorylation of CFL-1 by activated extracellular signal-regulated kinases 1 and 2 (ERK1/2) confers strong protection against HDAC inhibitor-induced cell injury. p-CFL-1 shows a loss of affinity with Bax and will not translocate to mitochondria, stably remaining in the cytoplasm. These results indicate that phosphorylation to inactivate CFL-1 decreased the chemosensitivity to HDAC inhibitors and resulting in drug resistance of HCC cells.
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.
authors.forename: P-H
authors.initials: PH
authors.lastname: Liao
authors.affiliation: Division of Colorectal Surgery, Mackay Memorial Hospital, Taipei, Taiwan.|Department of Mackay Medicine, Nursing and Management College, Taipei, Taiwan.
authors.forename: H-H
authors.initials: HH
authors.lastname: Hsu
authors.affiliation: Biomaterials Translational Research Center, China Medical University Hospital, Taichung, Taiwan.
authors.forename: T-S
authors.initials: TS
authors.lastname: Chen
authors.affiliation: Division of Colorectal Surgery, Taichung Veterans General Hospital, Taichung, Taiwan.
authors.forename: M-C
authors.initials: MC
authors.lastname: Chen
authors.affiliation: Department of Nursing, Mei Ho University, Pingtung, Taiwan.
authors.forename: C-H
authors.initials: CH
authors.lastname: Day
authors.affiliation: Division of Chest Medicine, Department of Internal Medicine, Armed Force Taichung General Hospital, Taichung, Taiwan.
authors.forename: C-C
authors.initials: CC
authors.lastname: Tu
authors.affiliation: Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan.
authors.forename: Y-M
authors.initials: YM
authors.lastname: Lin
authors.affiliation: Graduate Institute of Chinese Medical Science, China Medical University, Taichung, Taiwan.
authors.forename: F-J
authors.initials: FJ
authors.lastname: Tsai
authors.affiliation: Department of Biological Science and Technology, China Medical University, Taichung, Taiwan.
authors.forename: W-W
authors.initials: WW
authors.lastname: Kuo
authors.affiliation: Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.|Graduate Institute of Chinese Medical Science, China Medical University, Taichung, Taiwan.|Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan.
authors.forename: C-Y
authors.initials: CY
authors.lastname: Huang
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051338:Cofilin 1 / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000633:toxicity*; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D051338:Cofilin 1; D056572:Histone Deacetylase Inhibitors; D017382:Reactive Oxygen Species; D048049:Extracellular Signal-Regulated MAP Kinases