Involvement of ribonucleotide reductase-M1 in 5-fluorouracil‑induced DNA damage in esophageal cancer cell lines

Aoki,Yoshiro; Sakogawa,Kenji; Hihara,Jun; Emi,Manabu; Hamai,Yoichi; Kono,Kazuteru; Shi,Lin; Sun,Jiying; Kitao,Hiroyuki; Ikura,Tsuyoshi; Niida,Hiroyuki; Nakanishi,Makoto; Okada,Morihito; Tashiro,Satoshi

doi:10.3892/ijo.2013.1899

Involvement of ribonucleotide reductase-M1 in 5-fluorouracil‑induced DNA damage in esophageal cancer cell lines

Authors:
- Yoshiro Aoki
- Kenji Sakogawa
- Jun Hihara
- Manabu Emi
- Yoichi Hamai
- Kazuteru Kono
- Lin Shi
- Jiying Sun
- Hiroyuki Kitao
- Tsuyoshi Ikura
- Hiroyuki Niida
- Makoto Nakanishi
- Morihito Okada
- Satoshi Tashiro
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Affiliations: Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Minami-ku, Hiroshima, Japan, Department of Cellular Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Minami-ku, Hiroshima, Japan, Department of Molecular Oncology, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan, Department of Mutagenesis, Radiation Biology Center, Kyoto University, Sakyo-ku, Kyoto, Japan, Department of Molecular Biology, Hamamatsu University School of Medicine, Higashi-ku, Hamamatsu, Japan, Department of Experimental Pathology and Tumor Biology, Graduate School of Medical Sciences, Nagoya City University, Mizuho-ku, Nagoya, Japan
Published online on: April 16, 2013 https://doi.org/10.3892/ijo.2013.1899
Pages: 1951-1960

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Abstract

5-Fluorouracil (5-FU) is one of the most well established chemotherapeutic agents in the treatment of esophageal cancer. Ribonucleotide reductase M1 (RRM-1) is the rate‑limiting enzyme in de novo DNA synthesis, and has been considered to play an important role in the 5-FU metabolic pathway. However, the means by which RRM-1 participates in the anticancer effects of 5-FU and cisplatin (CDDP) have not been well studied. Here, we show that RRM-1 significantly contributes to the induction of DNA damage by 5-FU in esophageal cancer cell lines. An assay of γ-H2AX focus formation, a marker of DNA damage, after 5-FU treatment revealed good correlation with the levels of RRM-1 protein expression. Moreover, the increased sensitivity and RAD51 focus formation induced by the combination treatment of 5-FU and CDDP were significantly repressed by RRM-1 depletion. These results suggest that RRM-1 is involved not only in the induction of DNA damage by 5-FU but also in the synergistic cytotoxic effect in the combination therapy of 5-FU and CDDP.

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