Proteasome inhibitors remarkably prevent translesion replication in cancer cells but not normal cells.
When a replicative DNA polymerase encounters a lesion on the template strand and stalls, it is replaced with another polymerase(s) with low processivity that bypasses the lesion to continue DNA synthesis. This phenomenon is known as translesion replication or replicative bypass. Failing this, the cell is increasingly likely to undergo apoptosis. In this study, we found that proteasome inhibitors prevent translesion replication in human cancer cells but not in normal cells. Three proteasome inhibitors, MG-132, lactacystin, and MG-262, inhibited UV-induced translesion replication in a wide range of cancer cell lines, including HeLa, HGC-27, MCF-7, HepG2, WiDr, a malignant melanoma, an acute lymphoblastic leukemia, and a multiple myeloma cell line; irrespective of cell origin, histological type, or p53 status. In contrast, these inhibitors had little or no influence on normal fibroblasts (NB1RGB and TIG-1) or a normal liver mesenchymal (LI90) cell line. Among the DNA-damaging antineoplastic agents, cisplatin caused a UV-type translesion reaction; the proteasome inhibitors delayed cisplatin-induced translesion replication in cancer cell lines but had only a weak effect on normal cell lines. Therefore, translesion replication would be an effective target of proteasome inhibitors for cancer chemotherapy by which cancer cells can be efficiently sensitized to DNA-damaging antineoplastic agents, such as cisplatin.
Takezawa
Jun
J
Division of Genetic Biochemistry, The National Institute of Health and Nutrition, Shinjuku-ku, Tokyo 162-8636, Japan.
Ishimi
Yukio
Y
Yamada
Kouichi
K
D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D001897:Boronic Acids / Q000494:pharmacology; D002110:Caffeine / Q000494:pharmacology; D002478:Cells, Cultured; D002945:Cisplatin / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics*; D061988:Proteasome Inhibitors; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays
D001897:Boronic Acids; D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; C423917:MG 262; D061988:Proteasome Inhibitors; C067713:lactacystin; D002110:Caffeine; D002945:Cisplatin; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D000111:Acetylcysteine