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.
Highlights
Angiogenesis is a critical determinant of tumour growth and metastasis, as well as of wound healing, embryonic development, and arteriosclerosis[1]
Tumours, we developed a novel selective inhibitor of thymidine phosphorylase (TP) (TPI; 5-chloro-6-(2-iminopyrrolidin-1-yl) methyl-2,4 (1 H,3 H)-pyrimidinedione hydrochloride; Ki = 2 × 10−8 M)[7], which has several advantages over previously described inhibitors of TP. Using this TPI, we demonstrated that TP plays a key role in the invasiveness and metastasis of TP-expressing solid tumours, and suggested that TPI may be an anti-metastatic agent for blood-borne metastasis[8]
We reported that the mRNA and protein levels of IL-8 in TP-overexpressing human epidermoid carcinoma KB (KB/TP) cells were higher than those in KB (KB/CV) cells that were transfected with control vector (CV)[12]
Summary
Angiogenesis is a critical determinant of tumour growth and metastasis, as well as of wound healing, embryonic development, and arteriosclerosis[1]. Tumours, we developed a novel selective inhibitor of TP (TPI; 5-chloro-6-(2-iminopyrrolidin-1-yl) methyl-2,4 (1 H,3 H)-pyrimidinedione hydrochloride; Ki = 2 × 10−8 M)[7], which has several advantages over previously described inhibitors of TP Using this TPI, we demonstrated that TP plays a key role in the invasiveness and metastasis of TP-expressing solid tumours, and suggested that TPI may be an anti-metastatic agent for blood-borne metastasis[8]. Both TP and DR are involved in the production of reactive oxygen species (ROS) and increase the secretion of stress-induced angiogenic cytokines, such as vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP)-1, and interleukin (IL)-85,9,10. We investigated the molecular basis for ROS generation by TP
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