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ID 114957
Tabata, Sho Keio University
Yamamoto, Masatatsu Kagoshima University
Hirayama, Akiyoshi Keio University
Ohishi, Maki Keio University
Kuramoto, Takuya Tokushima University
Ikeda, Ryuji University of Miyazaki
Haraguchi, Misako Kagoshima University
Kawahara, Kohichi Kagoshima University
Shinsato, Yoshinari Kagoshima University
Minami, Kentaro Kagoshima University
Esumi, Hiroyasu Tokyo University of Science
Tomita, Masaru Keio University
Soga, Tomoyoshi Keio University
Furukawa, Tatsuhiko Kagoshima University
Akiyama, Shin-ichi National Kyushu Cancer Center
Content Type
Journal Article
Thymidine phosphorylase (TP) is a rate-limiting enzyme in the thymidine catabolic pathway. TP is identical to platelet-derived endothelial cell growth factor and contributes to tumour angiogenesis. TP induces the generation of reactive oxygen species (ROS) and enhances the expression of oxidative stress-responsive genes, such as interleukin (IL)-8. However, the mechanism underlying ROS induction by TP remains unclear. In the present study, we demonstrated that TP promotes NADPH oxidase-derived ROS signalling in cancer cells. NADPH oxidase inhibition using apocynin or small interfering RNAs (siRNAs) abrogated the induction of IL-8 and ROS in TP-expressing cancer cells. Meanwhile, thymidine catabolism induced by TP increased the levels of NADPH and intermediates of the pentose phosphate pathway (PPP). Both siRNA knockdown of glucose 6-phosphate dehydrogenase (G6PD), a rate-limiting enzyme in PPP, and a G6PD inhibitor, dihydroepiandrosterone, reduced TP-induced ROS production. siRNA downregulation of 2-deoxy-D-ribose 5-phosphate (DR5P) aldolase, which is needed for DR5P to enter glycolysis, also suppressed the induction of NADPH and IL-8 in TP-expressing cells. These results suggested that TP-mediated thymidine catabolism increases the intracellular NADPH level via the PPP, which enhances the production of ROS by NADPH oxidase and activates its downstream signalling.
Journal Title
Scientific Reports
Springer Nature
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Medical Sciences
University Hospital