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胸苷分解代谢促进 KB 和 yumoto 细胞中 NADPH 氧化酶衍生的活性氧（ROS）信号。

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

机构信息

Institute for Advanced Biosciences, Keio University, 246-2 Mizukami, Kakuganji, Tsuruoka, Yamagata, 997-0052, Japan.

Department of Molecular Oncology, Graduate School Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.

出版信息

Sci Rep. 2018 Apr 30;8(1):6760. doi: 10.1038/s41598-018-25189-y.

DOI:10.1038/s41598-018-25189-y
PMID:29713062
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5928239/
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.

摘要

胸苷磷酸化酶 (TP) 是胸苷分解代谢途径中的限速酶。TP 与血小板衍生的内皮细胞生长因子相同，有助于肿瘤血管生成。TP 诱导活性氧 (ROS) 的产生，并增强氧化应激反应基因的表达，如白细胞介素 (IL)-8。然而，TP 诱导 ROS 的机制尚不清楚。在本研究中，我们证明了 TP 促进了癌细胞中 NADPH 氧化酶衍生的 ROS 信号转导。使用 apocynin 或小干扰 RNA (siRNA) 抑制 NADPH 氧化酶可阻断 TP 表达的癌细胞中 IL-8 和 ROS 的诱导。同时，TP 诱导的胸苷分解代谢增加了 NADPH 和戊糖磷酸途径 (PPP) 中间产物的水平。siRNA 敲低 PPP 限速酶葡萄糖 6-磷酸脱氢酶 (G6PD) 和 G6PD 抑制剂二氢睾酮均可减少 TP 诱导的 ROS 产生。需要 DR5P 进入糖酵解的 2-脱氧-D-核糖 5-磷酸 (DR5P) 醛缩酶的 siRNA 下调也抑制了 TP 表达细胞中 NADPH 和 IL-8 的诱导。这些结果表明，TP 介导的胸苷分解代谢通过 PPP 增加了细胞内 NADPH 水平，从而增强了 NADPH 氧化酶产生 ROS 的能力，并激活了其下游信号转导。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1629/5928239/9b45423f19ad/41598_2018_25189_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1629/5928239/265af9f24e39/41598_2018_25189_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1629/5928239/2fc3105390c9/41598_2018_25189_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1629/5928239/0c76e7dceb0e/41598_2018_25189_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1629/5928239/9b45423f19ad/41598_2018_25189_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1629/5928239/265af9f24e39/41598_2018_25189_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1629/5928239/2fc3105390c9/41598_2018_25189_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1629/5928239/0c76e7dceb0e/41598_2018_25189_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1629/5928239/9b45423f19ad/41598_2018_25189_Fig4_HTML.jpg

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