Thymidine phosphorylase activates NFκB and stimulates the expression of angiogenic and metastatic factors in human cancer cells

Sho Tabata, Ryuji Ikeda, Masatatsu Yamamoto, Shunji Shimaoka, Naofumi Mukaida, Yasuo Takeda, Katsushi Yamada, Tomoyoshi Soga, Tatsuhiko Furukawa, Shin Ichi Akiyama

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12 Citations (Scopus)

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 IKKa/β protein levels, while promoting IκBa 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.

Original languageEnglish
Pages (from-to)10473-10485
Number of pages13
JournalOncotarget
Volume5
Issue number21
Publication statusPublished - 2014

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Keywords

  • IL-8
  • NFκB
  • ROS
  • Thymidine phosphorylase

ASJC Scopus subject areas

  • Oncology

Cite this

Tabata, S., Ikeda, R., Yamamoto, M., Shimaoka, S., Mukaida, N., Takeda, Y., Yamada, K., Soga, T., Furukawa, T., & Akiyama, S. I. (2014). Thymidine phosphorylase activates NFκB and stimulates the expression of angiogenic and metastatic factors in human cancer cells. Oncotarget, 5(21), 10473-10485.