Thymidine phosphorylase (TP), indentical to platelet-derived endothelial cell growth factor (PD-ECGF) is involved in not only pyrimidine metabolism but also in angiogenesis. TP is highly expressed in tumor tissue and known to be an independent factor of prognosis in several cancers irrespective of its angiogenic activity, suggesting that TP has other functions in cancer progression besides an angiogenic activity. We have previously reported that TP confers cytoprotective function against hypoxia and Fas on tumor cells. Therefore, we investigated the molecular mechanism of TP in the survival signal. Firstly, we measured TP promoter activity in human leukemia cell line, U937, under various stresses, and observed that DNA-damaging agents such as UV, cisplatin, doxorubicin, and VP-16 significantly enhanced not only the transcriptional activity of TP but also its protein expression. Next, we found that the cell lines stably transfected with TP cDNA (KB/TP, HCT-15/TP, and Jurkat/TP) were resistant to DNA damaging agents compared to each mock-transfected cell, and that the cytoprotective function of TP was independent of its enzymatic activity. Third, TP-overexpressing cells were prone to show high proportion of G1 fraction of cell cycle both in control and over apoptotic process, and also showed notable suppressions of ERK phosphorylations following apoptotic stimuli. In addition, all the TP-transfectants showed augmented AKT activation compared to mock-transfectants over the DNA damage-induced apoptotic process. The TP-induced resistance to apoptosis was significantly abrogated with PI3-kinase inhibitors. Taken together, all the findings indicate that the cytoprotective function of TP against DNA damage is dependent on the modifications of survival signal through regulations of PI3-kinase/Akt pathway.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]