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J Biol Chem, Vol. 273, Issue 24, 14707-14711, June 12, 1998
§,,
From the The cytotoxic anti-cancer purine nucleoside
analogs 2-chloro-2'-deoxyadenosine (CdA),
9- Division of Clinical Virology and
§ Division of Surgery, Karolinska Institute, Huddinge
University Hospital, S-14186 Stockholm, Sweden
-D-arabinofuranosylguanine (araG), and
2',2'-difluorodeoxyguanosine (dFdG) are phosphorylated by human
mitochondrial deoxyguanosine kinase (dGK) in vitro. We
overexpressed dGK as a fusion protein to the green fluorescent protein
in the human pancreatic cancer cell lines PanC-1 and MIA PaCa-2 to
determine the importance of dGK-mediated nucleoside analog
phosphorylation. The transfected cells showed mitochondrial
fluorescence patterns, and the mitochondrial locations of endogenous
and overexpressed dGK were verified by Western blot analysis of cell
extracts with polyclonal anti-dGK antibodies. The increase of dGK
activity in the overexpressing cells was ~4-fold. These cell lines
exhibited increased sensitivity to CdA, araG, and dFdG as compared with the untransfected parent cell lines. This is, to our knowledge, the
first demonstration of a correlation between the activity of a
mitochondrial deoxyribonucleoside kinase and the cytotoxicity of
nucleoside analogs. Our data imply that the dGK activity is rate-limiting for the efficacy of nucleoside analogs in the cell lines
investigated.
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