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

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.

• Authors: Sho Tabata, Masatatsu Yamamoto, Hisatsugu Goto, Akiyoshi Hirayama, Maki Ohishi, Takuya Kuramoto, Atsushi Mitsuhashi, Ryuji Ikeda, Misako Haraguchi, Kohichi Kawahara, Yoshinari Shinsato, Kentaro Minami, Atsuro Saijo, Yuko Toyoda, Masaki Hanibuchi, Yasuhiko Nishioka, Saburo Sone, Hiroyasu Esumi, Masaru Tomita, Tomoyoshi Soga, Tatsuhiko Furukawa, Shin-Ichi Akiyama
• Journal: Scientific reports (Sci Rep) Vol. 8 Issue 1 Pg. 6760 (04 30 2018) ISSN: 2045-2322 [Electronic] England
• PMID: 29713062 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-8
• RNA, Small Interfering
• Reactive Oxygen Species
• Dihydrotestosterone
• Glucosephosphate Dehydrogenase
• NADPH Oxidases
• TYMP protein, human
• Thymidine Phosphorylase
• Thymidine

Topics

• Cell Line, Tumor
• Dihydrotestosterone (pharmacology)
• Gene Knockout Techniques
• Glucosephosphate Dehydrogenase (antagonists & inhibitors, genetics)
• Humans
• Interleukin-8 (genetics)
• Metabolism (genetics)
• NADPH Oxidases (genetics, metabolism)
• Neoplasms (drug therapy, metabolism, pathology)
• Pentose Phosphate Pathway (genetics)
• RNA, Small Interfering (genetics)
• Reactive Oxygen Species (metabolism)
• Thymidine (metabolism)
• Thymidine Phosphorylase (genetics, metabolism)