Guanine nucleotide-binding protein 1 is one of the key molecules contributing to cancer cell radioresistance

Motoi Fukumoto, Tatsuya Amanuma, Yoshikazu Kuwahara, Tsutomu Shimura, Masatoshi Suzuki, Shiro Mori, Hiroyuki Kumamoto, Yohei Saito, Yasuhito Ohkubo, Zhenfeng Duan, Kenji Sano, Tomohiro Oguchi, Kazuyuki Kainuma, Shinichi Usami, Kengo Kinoshita, Inchul Lee, Manabu Fukumoto

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Standard fractionated radiotherapy for the treatment of cancer consists of daily irradiation of 2-Gy X-rays, 5 days a week for 5-8 weeks. To understand the characteristics of radioresistant cancer cells and to develop more effective radiotherapy, we established a series of novel, clinically relevant radioresistant (CRR) cells that continue to proliferate with 2-Gy X-ray exposure every 24 h for more than 30 days in vitro. We studied three human and one murine cell line, and their CRR derivatives. Guanine nucleotide-binding protein 1 (GBP1) gene expression was higher in all CRR cells than their corresponding parental cells. GBP1 knockdown by siRNA cancelled radioresistance of CRR cells in vitro and in xenotransplanted tumor tissues in nude mice. The clinical relevance of GBP1 was immunohistochemically assessed in 45 cases of head and neck cancer tissues. Patients with GBP1-positive cancer tended to show poorer response to radiotherapy. We recently reported that low dose long-term fractionated radiation concentrates cancer stem cells (CSCs). Immunofluorescence staining of GBP1 was stronger in CRR cells than in corresponding parental cells. The frequency of Oct4-positive CSCs was higher in CRR cells than in parental cells, however, was not as common as GBP1-positive cells. GBP1-positive cells were radioresistant, but radioresistant cells were not necessarily CSCs. We concluded that GBP1 overexpression is necessary for the radioresistant phenotype in CRR cells, and that targeting GBP1-positive cancer cells is a more efficient method in conquering cancer than targeting CSCs. Radioresistance tumors were GBP1 positive in clinicopathological specimens from head and neck cancer.

Original languageEnglish
Pages (from-to)1351-1359
Number of pages9
JournalCancer science
Volume105
Issue number10
DOIs
Publication statusPublished - 2014 Oct 1

Keywords

  • GTP-binding proteins
  • Head and neck neoplasms
  • Neoplasms
  • Radiation
  • Radiation oncology

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Fukumoto, M., Amanuma, T., Kuwahara, Y., Shimura, T., Suzuki, M., Mori, S., Kumamoto, H., Saito, Y., Ohkubo, Y., Duan, Z., Sano, K., Oguchi, T., Kainuma, K., Usami, S., Kinoshita, K., Lee, I., & Fukumoto, M. (2014). Guanine nucleotide-binding protein 1 is one of the key molecules contributing to cancer cell radioresistance. Cancer science, 105(10), 1351-1359. https://doi.org/10.1111/cas.12489