[Thymidine phosphorylase inhibits apoptosis induced by anticancer agents].
An angiogenic factor, platelet-derived endothelial cell growth factor/thymidine phosphorylase (PD-ECGF/TP), stimulates the chemotaxis of endothelial cells and confers resistance to apoptosis induced by hypoxia. 2-Deoxy-D-ribose, a degradation product of thymidine generated by TP enzymatic activity, partially prevented hypoxia-induced apoptosis. TP was expressed at higher levels in tumor tissuses compared to the adjacent non-neoplastic tissues in a variety of human carcinomas. High expression of TP is associated with an unfavorable prognosis. To investigate the effect of TP on cisplatin-induced apoptosis, human leukemia Jurkat cells were transfected wild-type or mutant (L148R) TP cDNA. TP inhibits a number of steps in the cisplatin-induced apoptotic pathway, activation of caspase 3, 9 and mitochondrial cytochrome c release. These findings suggest a mechanism by which TP confers the resistance to apoptosis by cisplatin. Moreover, mutant TP that has no enzymatic activity also suppressed cisplatin-induced apoptosis. These findings indicate that TP has cytoprotective functions against cytotoxic agents which are independent of its enzymatic activity.
Ikeda
Ryuji
R
Department of Clinical Pharmacy and Pharmacology, Department of Cancer Chemotherapy, Institute for Cancer Research, Graduate School of Medical and Dental Sciences, Kagoshima University 890-8520, Sakuragaoka 8-35-1, Japan.
Furukawa
Tatsuhiko
T
Sumizawa
Tomoyuki
T
Haraguchi
Misako
M
Oiso
Shigeru
S
Inoue
Ituro
I
Yamada
Katsushi
K
Akiyama
Shin-ichi
S
D000970:Antineoplastic Agents / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects*; D006801:Humans; D019169:Jurkat Cells; D013939:Thymidine Phosphorylase / Q000494:pharmacology*
D000970:Antineoplastic Agents; D013939:Thymidine Phosphorylase