Thymidine phosphorylase activates NFκB and stimulates the expression of angiogenic and metastatic factors in human cancer cells
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Sho Tabata1, Ryuji Ikeda2, Masatatsu Yamamoto3, Shunji Shimaoka4, Naofumi Mukaida5, Yasuo Takeda2, Katsushi Yamada6, Tomoyoshi Soga1, Tatsuhiko Furukawa3, Shin-ichi Akiyama7
1Institute for Advanced Biosciences, Keio University, Kakuganji, Tsuruoka, Yamagata 997-0052, Japan
2Department of Clinical Pharmacy and Pharmacology, Graduate School Medical and Dental Science, Kagoshima University, Kagoshima 890-8544, Japan
3Department of Molecular Oncology, Graduate School Medical and Dental Science, Kagoshima University, Kagoshima 890-8544, Japan
4Department of Gastroenterology, Nanpuh Hospital, Kagoshima 892-0854, Japan
5Department of Molecular Oncology, Cancer Research Institute, Kanazawa University, Kanazawa 920-0934, Japan
6Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Nagasaki International University, Sasebo, Nagasaki 859-3298, Japan
7Clinical Research Center, National Kyushu Cancer Center, Notame Minami-ku, Fukuoka 811-1395, Japan
Tatsuhiko Furukawa, e-mail: [email protected]
Shin-ichi Akiyama, e-mail: [email protected]
Keywords: thymidine phosphorylase, IL-8, ROS, NFκB
Received: May 20, 2014 Accepted: July 23, 2014 Published: December 01, 2014
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.
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