title: The role of T-fimbrin in the response to DNA damage: silencing of T-fimbrin by small interfering RNA sensitizes human liver cancer cells to DNA-damaging agents.
abstract: Fimbrins (also known as plastins) are actin-binding proteins of the cortical cytoskeleton present in all cells and conserved from yeast to mammals. We previously reported that the up-regulation of T-fimbrin, a fimbrin isoform, in association with G2 arrest following DNA damage and that a lack of T-fimbrin expression shortens the radiation-induced G2 arrest in Chinese hamster ovarian cells. In this study, we further investigated the role of T-fimbrin in DNA-damage response using a panel of human liver cancer cell lines and small interfering RNA technology. T-fimbrin was differentially expressed in human liver cancer cell lines. Colony formation assays revealed that cell lines lacking T-fimbrin expression were highly sensitive to DNA damage compared to cell lines that express T-fimbrin. Using siRNA designed to target T-fimbrin, we demonstrated that silencing endogenous T-fimbrin causes a marked increase in the cellular sensitivity to VP-16 and UV irradiation. Moreover, T-fimbrin deletion abrogated UV-mediated cell cycle checkpoint, and consequently led to increased apoptotic cell death in resistant cells. These findings suggest that the status of T-fimbrin expression may be a useful molecular marker for predicting the responsiveness of cancer cells to treatment with chemotherapeutic drugs.
authors.affiliation: The First Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ikeda
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Hiromu
authors.initials: H
authors.lastname: Suzuki
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mita
authors.forename: Minoru
authors.initials: M
authors.lastname: Toyota
authors.forename: Fumio
authors.initials: F
authors.lastname: Itoh
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Shinomura
authors.forename: Takashi
authors.initials: T
authors.lastname: Tokino
authors.forename: Kohzoh
authors.initials: K
authors.lastname: Imai
mesh_terms: D000199:Actins / Q000737:chemistry; D000970:Antineoplastic Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D002273:Carcinogens / Q000494:pharmacology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002469:Cell Separation; D003599:Cytoskeleton / Q000378:metabolism; D004249:DNA Damage; D019175:DNA Methylation; D000077209:Decitabine; D005047:Etoposide / Q000494:pharmacology; D005434:Flow Cytometry; D016195:G2 Phase; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D015151:Immunoblotting; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000502:physiology*; D008840:Microfilament Proteins / Q000502:physiology*; D008856:Microscopy, Fluorescence; D020033:Protein Isoforms; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014162:Transfection; D014466:Ultraviolet Rays
chemical_list: D000199:Actins; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D002273:Carcinogens; D008562:Membrane Glycoproteins; D008840:Microfilament Proteins; D020033:Protein Isoforms; D034741:RNA, Small Interfering; C026742:plastin; D005047:Etoposide; D000077209:Decitabine; D001374:Azacitidine