title: Interferon-α acts on the S/G2/M phases to induce apoptosis in the G1 phase of an IFNAR2-expressing hepatocellular carcinoma cell line.
abstract: Interferon-α (IFN-α) is used clinically to treat hepatocellular carcinoma (HCC), although the detailed therapeutic mechanisms remain elusive. In particular, IFN-α has long been implicated in control of the cell cycle, but its actual point of action has not been clarified. Here, using time lapse imaging analyses of the human HCC cell line HuH7 carrying a fluorescence ubiquitination-based cell cycle indicator (Fucci), we found that IFN-α induced cell cycle arrest in the G0/G1 phases, leading to apoptosis through an IFN-α type-2 receptor (IFNAR2)-dependent signaling pathway. Detailed analyses by time lapse imaging and biochemical assays demonstrated that the IFN-α/IFNAR2 axis sensitizes cells to apoptosis in the S/G2/M phases in preparation for cell death in the G0/G1 phases. In summary, this study is the first to demonstrate the detailed mechanism of IFN-α as an anticancer drug, using Fucci-based time lapse imaging, which will be informative for treating HCC with IFN-α in clinical practice.
authors.affiliation: From the Departments of Immunology and Cell Biology and Gastroenterological Surgery, Graduate School of Medicine and Frontier Biosciences, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan and.
authors.forename: Sakae
authors.initials: S
authors.lastname: Maeda
authors.affiliation: Gastroenterological Surgery, Graduate School of Medicine and Frontier Biosciences, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan and.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Wada
authors.affiliation: From the Departments of Immunology and Cell Biology and.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Naito
authors.affiliation: Gastroenterological Surgery, Graduate School of Medicine and Frontier Biosciences, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan and.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nagano
authors.affiliation: From the Departments of Immunology and Cell Biology and the Japan Science and Technology Agency, CREST, 5 Sanban-cho, Chiyoda-ku, Tokyo 102-0075, Japan.
authors.forename: Szandor
authors.initials: S
authors.lastname: Simmons
authors.affiliation: From the Departments of Immunology and Cell Biology and Gastroenterological Surgery, Graduate School of Medicine and Frontier Biosciences, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan and.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Kagawa
authors.affiliation: From the Departments of Immunology and Cell Biology and Gastroenterological Surgery, Graduate School of Medicine and Frontier Biosciences, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan and.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Naito
authors.affiliation: From the Departments of Immunology and Cell Biology and the Japan Science and Technology Agency, CREST, 5 Sanban-cho, Chiyoda-ku, Tokyo 102-0075, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Kikuta
authors.affiliation: From the Departments of Immunology and Cell Biology and.
authors.forename: Taeko
authors.initials: T
authors.lastname: Ishii
authors.affiliation: Gastroenterological Surgery, Graduate School of Medicine and Frontier Biosciences, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan and.
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Tomimaru
authors.affiliation: Gastroenterological Surgery, Graduate School of Medicine and Frontier Biosciences, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan and.
authors.forename: Naoki
authors.initials: N
authors.lastname: Hama
authors.affiliation: Gastroenterological Surgery, Graduate School of Medicine and Frontier Biosciences, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan and.
authors.forename: Koichi
authors.initials: K
authors.lastname: Kawamoto
authors.affiliation: Gastroenterological Surgery, Graduate School of Medicine and Frontier Biosciences, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan and.
authors.forename: Shogo
authors.initials: S
authors.lastname: Kobayashi
authors.affiliation: Gastroenterological Surgery, Graduate School of Medicine and Frontier Biosciences, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan and.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Eguchi
authors.affiliation: Gastroenterological Surgery, Graduate School of Medicine and Frontier Biosciences, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan and.
authors.forename: Koji
authors.initials: K
authors.lastname: Umeshita
authors.affiliation: Gastroenterological Surgery, Graduate School of Medicine and Frontier Biosciences, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan and.
authors.forename: Hideshi
authors.initials: H
authors.lastname: Ishii
authors.affiliation: Gastroenterological Surgery, Graduate School of Medicine and Frontier Biosciences, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan and.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Doki
authors.affiliation: Gastroenterological Surgery, Graduate School of Medicine and Frontier Biosciences, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan and mmori@gesrug.med.osaka-u.ac.jp.
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
authors.affiliation: From the Departments of Immunology and Cell Biology and the Japan Science and Technology Agency, CREST, 5 Sanban-cho, Chiyoda-ku, Tokyo 102-0075, Japan mishii@icb.med.osaka-u.ac.jp.
authors.forename: Masaru
authors.initials: M
authors.lastname: Ishii
mesh_terms: D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D017931:DNA Primers; D005434:Flow Cytometry; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D060888:Real-Time Polymerase Chain Reaction; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism*
chemical_list: D017931:DNA Primers; C508033:IFNAR2 protein, human; D016898:Interferon-alpha; D053633:Receptor, Interferon alpha-beta
keywords: Apoptosis; Cell Cycle; Cell Death; Fucci; Hepatocellular Carcinoma; Interferon