title: Involvement of ribonucleotide reductase-M1 in 5-fluorouracil‑induced DNA damage in esophageal cancer cell lines.
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.
authors.affiliation: Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Minami-ku, Hiroshima, Japan.
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Aoki
authors.forename: Kenji
authors.initials: K
authors.lastname: Sakogawa
authors.forename: Jun
authors.initials: J
authors.lastname: Hihara
authors.forename: Manabu
authors.initials: M
authors.lastname: Emi
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Hamai
authors.forename: Kazuteru
authors.initials: K
authors.lastname: Kono
authors.forename: Lin
authors.initials: L
authors.lastname: Shi
authors.forename: Jiying
authors.initials: J
authors.lastname: Sun
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kitao
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Ikura
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Niida
authors.forename: Makoto
authors.initials: M
authors.lastname: Nakanishi
authors.forename: Morihito
authors.initials: M
authors.lastname: Okada
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tashiro
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D045744:Cell Line, Tumor / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D004249:DNA Damage / Q000187:drug effects*; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D005472:Fluorouracil / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism; D012262:Ribonucleoside Diphosphate Reductase; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000964:Antimetabolites, Antineoplastic; C468783:H2AX protein, human; D006657:Histones; D025521:Tumor Suppressor Proteins; C475286:RRM1 protein, human; D012262:Ribonucleoside Diphosphate Reductase; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D002945:Cisplatin; D005472:Fluorouracil