Interferon-α acts on the S/G2/M phases to induce apoptosis in the G1 phase of an IFNAR2-expressing hepatocellular carcinoma cell line

Sakae Maeda, Hiroshi Wada, Yoko Naito, Hiroaki Nagano, Szandor Simmons, Yoshinori Kagawa, Atsushi Naito, Junichi Kikuta, Taeko Ishii, Yoshito Tomimaru, Naoki Hama, Koichi Kawamoto, Shogo Kobayashi, Hidetoshi Eguchi, Koji Umeshita, Hideshi Ishii, Yuichiro Doki, Masaki Mori, Masaru Ishii

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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 G 0/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.

Original languageEnglish
Pages (from-to)23786-23795
Number of pages10
JournalJournal of Biological Chemistry
Volume289
Issue number34
DOIs
Publication statusPublished - Jan 1 2014

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Maeda, S., Wada, H., Naito, Y., Nagano, H., Simmons, S., Kagawa, Y., Naito, A., Kikuta, J., Ishii, T., Tomimaru, Y., Hama, N., Kawamoto, K., Kobayashi, S., Eguchi, H., Umeshita, K., Ishii, H., Doki, Y., Mori, M., & Ishii, M. (2014). Interferon-α acts on the S/G2/M phases to induce apoptosis in the G1 phase of an IFNAR2-expressing hepatocellular carcinoma cell line. Journal of Biological Chemistry, 289(34), 23786-23795. https://doi.org/10.1074/jbc.M114.551879