Enhanced expression and activity of DNA polymerase beta in human ovarian tumor cells: impact on sensitivity towards antitumor agents.
DNA polymerase beta, one of the most inaccurate DNA synthesizing enzymes, has been shown to confer genetic instability when up-regulated in cells, a situation found in several human cancers. Here, we demonstrated that enhanced activity and expression of this enzyme occur in the human ovarian tumor 2008/C13*5.25 cells, which are resistant to the antitumor agent cisplatin and hypersensitive to 6-thioguanine. We found that translesion synthesis across platinated DNA crosslinks as well as increased incorporation into DNA of 6-thioguanine took place in the 2008/C13*5.25 cells compared to the parental 2008 cells. Such features being molecular signatures of DNA polymerase beta, these findings suggest that deregulation of its expression in cancer cells may contribute to the modulation of the response to antitumor treatments and therefore to tumor progression.
Bergoglio
V
V
Institut de Pharmacologie et de Biologie Structurale, UMR CNRS 5089, 205 route de Narbonne, 31077 Toulouse cedex, France.
Canitrot
Y
Y
Hogarth
L
L
Minto
L
L
Howell
S B
SB
Cazaux
C
C
Hoffmann
J S
JS
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D002851:Chromatography, High Pressure Liquid; D002945:Cisplatin / Q000494:pharmacology; D003432:Cross-Linking Reagents / Q000494:pharmacology; D018736:DNA Adducts; D019951:DNA Polymerase beta / Q000096:biosynthesis* / Q000378:metabolism*; D004260:DNA Repair; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000201:enzymology*; D010641:Phenotype; D013866:Thioguanine / Q000494:pharmacology; D015854:Up-Regulation
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D018736:DNA Adducts; D019951:DNA Polymerase beta; D013866:Thioguanine; D002945:Cisplatin