title: A compensatory role of NF-κB to p53 in response to 5-FU-based chemotherapy for gastric cancer cell lines.
abstract: Despite of remarkable improvement of postoperative 5-FU-based adjuvant chemotherapy, the relapse rate of gastric cancer patients who undergo curative resection followed by the adjuvant chemotherapy remains substantial. Therefore, it is important to identify prediction markers for the chemotherapeutic efficacy of 5-FU. We recently identified NF-κB as a candidate relapse prediction biomarker in gastric cancer. To evaluate the biological significance of NF-κB in the context of 5-FU-based chemotherapy, we analyzed the NF-κB-dependent biological response upon 5-FU treatment in gastric cancer cell lines. Seven genes induced by 5-FU treatment in an NF-κB-dependent manner were identified, five of which are known p53 targets. Knockdown of RELA, which encodes the p65 subunit of NF-κB, decreased both p53 and p53 target protein levels. In contrast, NF-κB was not affected by TP53 knockdown. We also demonstrated that cell lines bearing Pro/Pro homozygosity in codon72 of p53 exon4, which is important for NF-κB binding to p53, are more resistant to 5-FU than those with Arg/Arg homozygosity. We conclude that NF-κB plays an important role in the response to 5-FU treatment in gastric cancer cell lines, with a possible compensatory function of p53. These results suggest that NF-κB is a potential 5-FU-chemosensitivity prediction marker that may reflect 5-FU-induced stress-response pathways, including p53.
authors.affiliation: Molecular Therapeutics Laboratory, Iwate Medical University School of Medicine, Morioka, Japan ; Department of Surgery, Iwate Medical University School of Medicine, Morioka, Japan.
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Endo
authors.affiliation: Molecular Therapeutics Laboratory, Iwate Medical University School of Medicine, Morioka, Japan ; Department of Surgery, Iwate Medical University School of Medicine, Morioka, Japan ; MIAST (Medical Innovation by Advanced Science and Technology) project, Iwate Medical University, Morioka, Japan ; Institute for Biomedical Sciences, Iwate Medical University, Yahaba, Japan.
authors.forename: Satoshi S
authors.initials: SS
authors.lastname: Nishizuka
authors.affiliation: Molecular Therapeutics Laboratory, Iwate Medical University School of Medicine, Morioka, Japan ; Department of Surgery, Iwate Medical University School of Medicine, Morioka, Japan ; MIAST (Medical Innovation by Advanced Science and Technology) project, Iwate Medical University, Morioka, Japan ; Institute for Biomedical Sciences, Iwate Medical University, Yahaba, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Kume
authors.affiliation: Molecular Therapeutics Laboratory, Iwate Medical University School of Medicine, Morioka, Japan ; Department of Surgery, Iwate Medical University School of Medicine, Morioka, Japan.
authors.forename: Kazushige
authors.initials: K
authors.lastname: Ishida
authors.affiliation: Molecular Therapeutics Laboratory, Iwate Medical University School of Medicine, Morioka, Japan ; Department of Surgery, Iwate Medical University School of Medicine, Morioka, Japan.
authors.forename: Hirokatsu
authors.initials: H
authors.lastname: Katagiri
authors.affiliation: Molecular Therapeutics Laboratory, Iwate Medical University School of Medicine, Morioka, Japan ; Department of Surgery, Iwate Medical University School of Medicine, Morioka, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Ishida
authors.affiliation: Molecular Therapeutics Laboratory, Iwate Medical University School of Medicine, Morioka, Japan ; Department of Surgery, Iwate Medical University School of Medicine, Morioka, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Sato
authors.affiliation: Molecular Therapeutics Laboratory, Iwate Medical University School of Medicine, Morioka, Japan ; Department of Surgery, Iwate Medical University School of Medicine, Morioka, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwaya
authors.affiliation: Department of Surgery, Iwate Medical University School of Medicine, Morioka, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Koeda
authors.affiliation: Department of Surgery, Iwate Medical University School of Medicine, Morioka, Japan.
authors.forename: Go
authors.initials: G
authors.lastname: Wakabayashi
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003062:Codon; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005472:Fluorouracil / Q000494:pharmacology* / Q000627:therapeutic use; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000964:Antimetabolites, Antineoplastic; D003062:Codon; D016328:NF-kappa B; D051996:Transcription Factor RelA; D016159:Tumor Suppressor Protein p53; D005472:Fluorouracil