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Journal of Biochemistry 2004 136(5):733-740; doi:10.1093/jb/mvh180
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© 2004 The Japanese Biochemical Society

BIOCHEMISTRY

Gene-Expression Profiling Reveals Down-Regulation of Equilibrative Nucleoside Transporter 1 (ENT1) in Ara-C–Resistant CCRF-CEM–Derived Cells

Kazuchika Takagaki*, Susumu Katsuma, Yoshinori Kaminishi, Tatsuya Horio, Shinichiro Nakagawa, Teruo Tanaka, Tadaaki Ohgi and Junichi Yano

Discovery Research Laboratories, Nippon Shinyaku Co., Ltd, 3-14-1 Sakura, Tsukuba, Ibaraki 305-0003

We have investigated the mechanism of resistance of leukemia cells to Ara-C using an in-house cDNA microarray designed for the analysis of leukemia cells. We produced Ara-C–resistant cells from the CCRF-CEM (acute lymphoblastic leukemia) cell line and compared their gene-expression profile with that of wild-type cells. The adenosine deaminase (ADA) gene was highly up-regulated in Ara-C–resistant cells, while equilibrative nucleoside transporter 1 (ENT1) and several cell-cycle–related genes were down-regulated. Of all these genes, ENT1 seemed the most likely to be relevant to Ara-C resistance. To investigate the role of ENT1 in Ara-C–resistant cells, we transfected the cells with the gene. ENT1-transfected Ara-C–resistant cells resembled wild-type CCRF-CEM cells more closely than untransfected Ara-C–resistant cells in terms of growth rate, Ara-C-uptake characteristics, and ADA expression levels. The down-regulation of the ENT1 gene is expected to result in nucleotide deficiency in addition to blockage of Ara-C influx. Accordingly, Ara-C–resistant cells showed low growth rates, which were restored by transfection with ENT1. These low growth rates were also correlated with the phosphorylation level of cell-cycle checkpoint kinase 2. In this study we identified down-regulation of ENT1 as the factor responsible for Ara-C resistance, and this knowledge may be used to devise a clinical regimen that will overcome the resistance.

* To whom correspondence should be addressed. Phone: +81-29-850-6242, Fax: +81-29-850-6217, E-mail: k.takagaki{at}nippon-shinyaku.co.jp


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