Effect of a poly(ADP-ribose) polymerase-1 inhibitor against esophageal squamous cell carcinoma cell lines

Authors

  • Tomomitsu Nasuno,

    1. Division of Translational Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan
    2. Department of Otorhinolaryngology, University of Kitasato Hospital, Minami-ku, Sagamihara, Kanagawa, Japan
    Search for more papers by this author
  • Sachiyo Mimaki,

    1. Division of Translational Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan
    Search for more papers by this author
  • Makito Okamoto,

    1. Department of Otorhinolaryngology, University of Kitasato Hospital, Minami-ku, Sagamihara, Kanagawa, Japan
    Search for more papers by this author
  • Hiroyasu Esumi,

    1. Division of Translational Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan
    2. Research Institute for Biological Sciences, Tokyo University of Science, Noda, Chiba, Japan
    Search for more papers by this author
  • Katsuya Tsuchihara

    Corresponding author
    1. Division of Translational Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, Japan
    • Correspondence

      Katsuya Tsuchihara, Division of Translational Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan.

      Tel: +81-4-7133-1111; Fax: +81-4-7134-8786;

      E-mail: ktsuchih@east.ncc.go.jp

    Search for more papers by this author

  • Funding Information

    National Cancer Center Research and Development Fund (23-A-8, 15). Third Term Comprehensive 10-year Strategy for Cancer Control from the Ministry of Health, Labour and Welfare (H22-033).

Abstract

Effective molecular target drugs that improve therapeutic efficacy with fewer adverse effects for esophageal cancer are highly anticipated. Poly(ADP-ribose) polymerase (PARP) inhibitors have been proposed as low-toxicity agents to treat double strand break (DSB)-repair defective tumors. Several findings imply the potential relevance of DSB repair defects in the tumorigenesis of esophageal squamous cell carcinoma (ESCC). We evaluated the effect of a PARP Inhibitor (AZD2281) on the TE-series ESCC cell lines. Of these eight cell lines, the clonogenic survival of one (TE-6) was reduced by AZD2281 to the level of DSB repair-defective Capan-1 and HCC1937 cells. AZD2281-induced DNA damage was implied by increases in γ-H2AX and cell cycle arrest at G2/M phase. The impairment of DSB repair in TE-6 cells was suggested by a sustained increase in γ-H2AX levels and the tail moment calculated from a neutral comet assay after X-ray irradiation. Because the formation of nuclear DSB repair protein foci was impaired in TE-6 cells, whole-exome sequencing of these cells was performed to explore the gene mutations that might be responsible. A novel mutation in RNF8, an E3 ligase targeting γ-H2AX was identified. Consistent with this, polyubiquitination of γ-H2AX after irradiation was impaired in TE-6 cells. Thus, AZD2281 induced growth retardation of the DSB repair-impaired TE-6 cells. Interestingly, a strong correlation between basal expression levels of γ-H2AX and sensitivity to AZD2281was observed in the TE-series cells (R2 = 0.5345). Because the assessment of basal DSB status could serve as a biomarker for selecting PARP inhibitor-tractable tumors, further investigation is warranted.

Ancillary