title: 5-Fluorouracil up-regulates interferon pathway gene expression in esophageal cancer cells.
abstract: 5-Fluorouracil (FU) is a chemotherapeutic agent commonly used against esophageal cancer. Recently, interferons (IFNs) have been administered together with cytotoxic chemotherapy to patients with this cancer, although the mechanisms of synergy are unknown. We reconsidered the mechanisms for the effects of 5-FU in this context, aiming to refine combination therapy. After three cell lines (T.T, TE-2, and TE-6), derived from human esophageal squamous cell carcinoma (SCC), were exposed to 5-FU, the expression profiles were analyzed using high-density oligonucleotide microarrays representing about 12,000 genes. Among them, three IFN-related genes, an IFN receptor gene (IFNAR2) and two IFN-stimulated genes (ISG15K, ISG-54K), that were up-regulated following addition of 5-FU, were investigated. Up-regulation was confirmed by RT-PCR. Based on these results, the antitumor effects of exposure to 5-FU simultaneously with IFN-alpha, -beta and -gamma were investigated. The growth of esophageal SCC cells with 5-FU was suppressed synergistically or semi-additively by IFN-alpha and -beta, but not by IFN-gamma. These findings indicated that 5-FU stimulated IFN pathways in esophageal SCC cells following up-regulation of the IFN type I receptor. A combination of 5-FU and an IFN, therefore, may be particularly efficacious in esophageal cancer.
authors.affiliation: Department of Surgical Oncology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, 545-8585 Osaka, Japan.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Matsumura
authors.forename: Masakazu
authors.initials: M
authors.lastname: Yashiro
authors.forename: Masaichi
authors.initials: M
authors.lastname: Ohira
authors.forename: Hisahiro
authors.initials: H
authors.lastname: Tabuchi
authors.forename: Kosei
authors.initials: K
authors.lastname: Hirakawa
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics*; D004357:Drug Synergism; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007372:Interferons / Q000008:administration & dosage / Q000494:pharmacology*; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D016601:RNA-Binding Proteins; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon / Q000096:biosynthesis / Q000235:genetics*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D014452:Ubiquitins / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D051017:Apoptosis Regulatory Proteins; D016207:Cytokines; C484289:IFIT2 protein, human; C508033:IFNAR2 protein, human; D008565:Membrane Proteins; D016601:RNA-Binding Proteins; D017471:Receptors, Interferon; D014157:Transcription Factors; D014452:Ubiquitins; D053633:Receptor, Interferon alpha-beta; C074034:ISG15 protein, human; D007372:Interferons; D005472:Fluorouracil