title: Thymidine phosphorylase activates NFκB and stimulates the expression of angiogenic and metastatic factors in human cancer cells.
abstract: Thymidine phosphorylase (TP) promotes angiogenesis and metastasis, and confers resistance to anticancer agents in some cancer cell types. We previously reported that TP stimulates the expression of interleukin (IL)-8 in human KB cancer cells by an unknown mechanism. A mutation in the nuclear factor (NF)κB binding site of the IL-8 promoter suppressed promoter activity in KB/TP cells that overexpress TP. Specifically inhibiting NFκB by using BY11-7082 also suppressed TP-induced IL-8 promoter activity and IL-8 expression. Moreover, TP overexpression led to the activation of NFκB and an upregulation in the expression of its target genes, and increased phosphorylated IKKα/β protein levels, while promoting IκBα degradation as well as p65 phosphorylation and nuclear localization. The activation of NFκB in KB/TP cells was suppressed by the antioxidants N-acetylcysteine and EUK-8. In addition, in gastric cancer tissue samples, the expression of the NFκB-regulated genes, including IL-8, IL-6, and fibronectin-1 was positively correlated with TP expression. These findings indicate that reactive oxygen species mediated NFκB activation by TP increases the expression of genes that promote angiogenesis and metastasis in gastric cancer.
authors.affiliation: Institute for Advanced Biosciences, Keio University, Kakuganji, Tsuruoka, Yamagata 997-0052, Japan.
authors.forename: Sho
authors.initials: S
authors.lastname: Tabata
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, Graduate School Medical and Dental Science, Kagoshima University, Kagoshima 890-8544, Japan.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Ikeda
authors.affiliation: Department of Molecular Oncology, Graduate School Medical and Dental Science, Kagoshima University, Kagoshima 890-8544, Japan.
authors.forename: Masatatsu
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Department of Gastroenterology, Nanpuh Hospital, Kagoshima 892-0854, Japan.
authors.forename: Shunji
authors.initials: S
authors.lastname: Shimaoka
authors.affiliation: Department of Molecular Oncology, Cancer Research Institute, Kanazawa University, Kanazawa 920-0934, Japan.
authors.forename: Naofumi
authors.initials: N
authors.lastname: Mukaida
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, Graduate School Medical and Dental Science, Kagoshima University, Kagoshima 890-8544, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Takeda
authors.affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Nagasaki International University, Sasebo, Nagasaki 859-3298, Japan.
authors.forename: Katsushi
authors.initials: K
authors.lastname: Yamada
authors.affiliation: Institute for Advanced Biosciences, Keio University, Kakuganji, Tsuruoka, Yamagata 997-0052, Japan.
authors.forename: Tomoyoshi
authors.initials: T
authors.lastname: Soga
authors.affiliation: Department of Molecular Oncology, Graduate School Medical and Dental Science, Kagoshima University, Kagoshima 890-8544, Japan.
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Furukawa
authors.affiliation: Clinical Research Center, National Kyushu Cancer Center, Notame Minami-ku, Fukuoka 811-1395, Japan.
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Akiyama
mesh_terms: D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009389:Neovascularization, Pathologic; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D013939:Thymidine Phosphorylase / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
chemical_list: D005353:Fibronectins; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D012333:RNA, Messenger; D013939:Thymidine Phosphorylase