Thymidine catabolism promotes NADPH oxidase-derived reactive oxygen species (ROS) signalling in KB and yumoto cells

• Published in: Scientific reports Vol. 8; no. 1; pp. 6760 - 8
• Main Authors: Tabata, Sho, Yamamoto, Masatatsu, Goto, Hisatsugu, Hirayama, Akiyoshi, Ohishi, Maki, Kuramoto, Takuya, Mitsuhashi, Atsushi, Ikeda, Ryuji, Haraguchi, Misako, Kawahara, Kohichi, Shinsato, Yoshinari, Minami, Kentaro, Saijo, Atsuro, Toyoda, Yuko, Hanibuchi, Masaki, Nishioka, Yasuhiko, Sone, Saburo, Esumi, Hiroyasu, Tomita, Masaru, Soga, Tomoyoshi, Furukawa, Tatsuhiko, Akiyama, Shin-Ichi
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 30.04.2018; Nature Publishing Group UK; Nature Portfolio
• Subjects: Angiogenesis; Cancer; D-Ribose; Endothelial cells; Enzymes; Glucosephosphate dehydrogenase; Glycolysis; Interleukin 8; Intermediates; NAD(P)H oxidase; Oxidative stress; Pentose phosphate pathway; Phosphorylase; Platelet-derived endothelial cell growth factor; Reactive oxygen species; Ribose; Signal transduction; siRNA; Thymidine; Thymidine phosphorylase; Tumors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-25189-y

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.