Sensitivity of human cancer cells to the new anticancer ribo-nucleoside TAS-106 is correlated with expression of uridine-cytidine kinase 2.
TAS-106 [1-(3-C-ethynyl-beta-D-ribo-pentofuranosyl)cytosine] is a new anticancer ribo-nucleoside with promising antitumor activity. We have previously presented evidence suggesting that the TAS-106 sensitivity of cells is correlated with intracellular accumulation of the triphosphate of TAS-106, which may be affected both by cellular membrane transport mechanisms and uridine-cytidine kinase (UCK) activity. Since the presence of a UCK family consisting of two members, UCK1 and UCK2, has recently been reported in human cells, we investigated the relation between expression of UCK1 and UCK2 at both the mRNA and protein levels and UCK activity (TAS-106 phosphorylation activity) in a panel of 10 human cancer cell lines. Measurement of UCK activity in these cell lines revealed that it was well correlated with the cells' sensitivity to TAS-106. In addition, the mRNA or protein expression level of UCK2 was closely correlated with UCK activity in these cell lines, but neither the level of expression of UCK1 mRNA nor that of protein was correlated with enzyme activity. We therefore compared the protein expression level of UCK2 in several human tumor tissues and the corresponding normal tissues. Expression of UCK2 protein was barely detectable in 4 of the 5 human tumor tissues, but tended to be high in the pancreatic tumor tissue. It could not be detected at all in any of the normal tissues. Thus, expression of UCK2 appeared to be correlated with cellular sensitivity to TAS-106, and it may contribute to the tumor-selective cytotoxicity of TAS-106.
Shimamoto
Yuji
Y
Hanno Research Center, Taiho Pharmaceutical Co., Ltd., Hanno, Saitama 357-8527, Japan. simamoto@taiho.co.jp
Koizumi
Katsuhisa
K
Okabe
Hiroyuki
H
Kazuno
Hiromi
H
Murakami
Yuko
Y
Nakagawa
Fumio
F
Matsuda
Akira
A
Sasaki
Takuma
T
Fukushima
Masakazu
M
D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D003562:Cytidine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D003600:Cytosol / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D009703:Nucleoside-Phosphate Kinase / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D014541:Uridine Kinase / Q000378:metabolism
C103084:1-(3-C-ethynylribopentofuranosyl)cytosine; D000970:Antineoplastic Agents; D012333:RNA, Messenger; D003562:Cytidine; D014541:Uridine Kinase; C019979:cytidylate kinase; D009703:Nucleoside-Phosphate Kinase