title: Guanine nucleotide-binding protein 1 is one of the key molecules contributing to cancer cell radioresistance.
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.
authors.affiliation: Department of Pathology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
authors.forename: Motoi
authors.initials: M
authors.lastname: Fukumoto
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Amanuma
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Kuwahara
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Shimura
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Suzuki
authors.forename: Shiro
authors.initials: S
authors.lastname: Mori
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kumamoto
authors.forename: Yohei
authors.initials: Y
authors.lastname: Saito
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Ohkubo
authors.forename: Zhenfeng
authors.initials: Z
authors.lastname: Duan
authors.forename: Kenji
authors.initials: K
authors.lastname: Sano
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Oguchi
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Kainuma
authors.forename: Shinichi
authors.initials: S
authors.lastname: Usami
authors.forename: Kengo
authors.initials: K
authors.lastname: Kinoshita
authors.forename: Inchul
authors.initials: I
authors.lastname: Lee
authors.forename: Manabu
authors.initials: M
authors.lastname: Fukumoto
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D019204:GTP-Binding Proteins / Q000032:analysis / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008875:Middle Aged; D009369:Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D014411:Neoplastic Stem Cells / Q000528:radiation effects*; D050814:Octamer Transcription Factor-3 / Q000032:analysis; D020411:Oligonucleotide Array Sequence Analysis; D011836:Radiation Tolerance
chemical_list: C490287:GBP1 protein, human; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D019204:GTP-Binding Proteins
keywords: GTP-binding proteins; head and neck neoplasms; neoplasms; radiation; radiation oncology
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