1. Thymidine catabolism promotes NADPH oxidase-derived reactive oxygen species (ROS) signalling in KB and yumoto cells.
- Author
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Tabata S, Yamamoto M, Goto H, Hirayama A, Ohishi M, Kuramoto T, Mitsuhashi A, Ikeda R, Haraguchi M, Kawahara K, Shinsato Y, Minami K, Saijo A, Toyoda Y, Hanibuchi M, Nishioka Y, Sone S, Esumi H, Tomita M, Soga T, Furukawa T, and Akiyama SI
- Subjects
- Cell Line, Tumor, Dihydrotestosterone pharmacology, Gene Knockout Techniques, Glucosephosphate Dehydrogenase antagonists & inhibitors, Humans, Interleukin-8 genetics, Metabolism genetics, NADPH Oxidases genetics, Neoplasms drug therapy, Neoplasms pathology, Pentose Phosphate Pathway genetics, RNA, Small Interfering genetics, Reactive Oxygen Species metabolism, Thymidine Phosphorylase metabolism, Glucosephosphate Dehydrogenase genetics, NADPH Oxidases metabolism, Neoplasms metabolism, Thymidine metabolism, Thymidine Phosphorylase genetics
- Abstract
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.
- Published
- 2018
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