Thymidine phosphorylase induces carcinoma cell oxidative stress and promotes secretion of angiogenic factors.
Thymidine phosphorylase (TP) (E.C. 2.4.2.4), also known as platelet-derived endothelial cell growth factor, is a potent angiogenic factor. The expression of TP correlates with poor prognosis in a range of tumor types. 2-Deoxy-D-ribose-1-phosphate, a product of thymidine catabolism by TP, is a strongly reducing sugar that generates oxygen radical species during the early stages of protein glycation. We show that thymidine induces oxidative stress in TP-overexpressing carcinoma cells, promoting secretion of the stress-induced angiogenic factors vascular endothelial growth factor and interleukin-8, and inducing matrix metalloproteinase-1. Our findings outline a putative mechanism for TP-induced angiogenesis and identify novel targets for intervention.
Brown
N S
NS
Molecular Angiogenesis Laboratory, Imperial Cancer Research Fund, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, United Kingdom.
Jones
A
A
Fujiyama
C
C
Harris
A L
AL
Bicknell
R
R
D002277:Carcinoma / Q000098:blood supply / Q000201:enzymology* / Q000378:metabolism; D016228:Endothelial Growth Factors / Q000096:biosynthesis / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis / Q000378:metabolism*; D008222:Lymphokines / Q000096:biosynthesis / Q000378:metabolism*; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000201:enzymology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D013936:Thymidine / Q000378:metabolism / Q000494:pharmacology; D013939:Thymidine Phosphorylase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000098:blood supply / Q000201:enzymology* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D016209:Interleukin-8; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D013939:Thymidine Phosphorylase; D020781:Matrix Metalloproteinase 1; D013936:Thymidine