Protection against DNA damage-induced apoptosis by the angiogenic factor thymidine phosphorylase.
Thymidine phosphorylase (TP) is involved both in pyrimidine nucleoside metabolism and in angiogenesis. TP also conferred the resistance to hypoxia-induced apoptosis of the cancer cells. In U937 cells, DNA damage-inducing agents significantly enhanced the expression of TP. Cell lines stably transfected with TP cDNA were more resistant to the DNA damage-inducing agents than the mock-transfected cells and showed augmented activity of Akt. The cytoprotective function of TP against DNA damage was independent of its enzymatic activity. The resistance to apoptosis was partially abrogated by treatment with the phosphatidyl inositol 3-kinase (PI3K) inhibitors, suggesting that the cytoprotective function of TP is mediated, at least in part, by regulation of the PI3K/Akt pathway. These findings indicate that TP expression in increased by various stress including DNA damage and that TP molecules confer resistance to DNA damage-induced apoptosis in cancer cells.
Jeung
Hei-Cheul
HC
Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima 890-8520, Japan.
Che
Xiao-Fang
XF
Haraguchi
Misako
M
Zhao
Hong-Ye
HY
Furukawa
Tatsuhiko
T
Gotanda
Takenari
T
Zheng
Chun-Lei
CL
Tsuneyoshi
Kengo
K
Sumizawa
Tomoyuki
T
Roh
Jae Kyung
JK
Akiyama
Shin-Ichi
S
D043925:Angiogenesis Inducing Agents; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology; D017209:Apoptosis; D002460:Cell Line; D004249:DNA Damage; D016193:G1 Phase; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D013939:Thymidine Phosphorylase / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D016159:Tumor Suppressor Protein p53
D043925:Angiogenesis Inducing Agents; D000970:Antineoplastic Agents; D016159:Tumor Suppressor Protein p53; D013939:Thymidine Phosphorylase; D019869:Phosphatidylinositol 3-Kinases