Thymidine phosphorylase inhibits apoptosis induced by cisplatin.
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, partially prevents hypoxia-induced apoptosis. TP is expressed at higher levels in tumor tissues 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 with wild-type or mutant (L148R) TP cDNA. TP inhibited a number of steps in the cisplatin-induced apoptotic pathway, activation of caspases 3 and 9 and mitochondrial cytochrome c release. These findings suggest a mechanism by which TP confers resistance to apoptosis induced 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 Cancer Chemotherapy, Institute for Cancer Research, Faculty of Medicine, Kagoshima University, Sakuragaoka 8-35-1, Kagoshima 890, Japan.
Furukawa
Tatsuhiko
T
Mitsuo
Ryoichi
R
Noguchi
Tomohiro
T
Kitazono
Masaki
M
Okumura
Hiroshi
H
Sumizawa
Tomoyuki
T
Haraguchi
Misako
M
Che
Xiao-Fang
XF
Uchimiya
Hiroshi
H
Nakajima
Yuich
Y
Ren
Xiao Qin
XQ
Oiso
Shigeru
S
Inoue
Ituro
I
Yamada
Katsushi
K
Akiyama
Shin-ichi
S
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D002458:Cell Fractionation; D002945:Cisplatin / Q000494:pharmacology*; D003574:Cytochrome c Group / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D004789:Enzyme Activation; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D019169:Jurkat Cells; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013939:Thymidine Phosphorylase / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein
D000970:Antineoplastic Agents; D003574:Cytochrome c Group; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D005047:Etoposide; D004317:Doxorubicin; D013939:Thymidine Phosphorylase; D020169:Caspases; D002945:Cisplatin