Multifunctional role of thymidine phosphorylase in cancer

Thymidine phosphorylase (TP) supports multiple procancer processes, including cell division, angiogenesis, protein glycation, alternative metabolism, and survival. In cancer, the TP-mediated catabolism of thymidine is dominant and the 2-deoxyribose (2dDR) formed from 2-deoxy-α-D-ribose-1-phosphate (2dDR1P) can generate a chemotactic gradient stimulating angiogenesis, glycate proteins altering their function, and can be metabolized to glyceraldehyde 3-phosphate (G3P) as a substrate for glycolysis or the pentose phosphate pathway (PPP). The high levels of TP expression in cancer have been exploited to bioactivate 5-fluorouracil (5-FU) prodrugs at the site of the cancer. TP inhibitors hold promise as anticancer agents as they disrupt multiple TP-mediated processes but have had limited success due to rapid clearance. Recently, it has been reported that TP can form protein–protein complexes with Src family of tyrosine kinases (SFKs), specifically Lyn kinase, which may support a procancer role for TP independent of its catalytic activity. Thymidine phosphorylase (TP) catalyzes the reversible phosphorolysis of thymidine, maintaining nucleoside homeostasis for DNA repair and replication. In many cancers TP is expressed at high levels and promotes thymidine catabolism, ultimately generating 2-deoxyribose (2dDR) that can support multiple procancer processes, including glycation of proteins, alternative metabolism, extracellular matrix remodeling, and angiogenesis. Therefore, inhibition of TP is an attractive anticancer strategy; however, an alternative approach that exploits the catalytic activity of TP to activate 5-fluorouracil (5-FU) prodrugs has been clinically successful. Here, we review the structure, function, and regulation of TP, its multiple supporting roles in cancer growth and survival. We summarize TP inhibitor and prodrug development and propose TP-targeting strategies that could potentiate the action of current therapies. Thymidine phosphorylase (TP) catalyzes the reversible phosphorolysis of thymidine, maintaining nucleoside homeostasis for DNA repair and replication. In many cancers TP is expressed at high levels and promotes thymidine catabolism, ultimately generating 2-deoxyribose (2dDR) that can support multiple procancer processes, including glycation of proteins, alternative metabolism, extracellular matrix remodeling, and angiogenesis. Therefore, inhibition of TP is an attractive anticancer strategy; however, an alternative approach that exploits the catalytic activity of TP to activate 5-fluorouracil (5-FU) prodrugs has been clinically successful. Here, we review the structure, function, and regulation of TP, its multiple supporting roles in cancer growth and survival. We summarize TP inhibitor and prodrug development and propose TP-targeting strategies that could potentiate the action of current therapies.