The molecular mechanisms of 5-fluoro-2'-deoxyuridine induced cell death.
The molecular mechanism of cell death induced by 5-Fluoro-2'-deoxyuridine (FUdR) was investigated. FUdR caused cell death to induce dNTP pool imbalance and following DNA double strand breaks in mouse mammary tumor FM3A cells. We isolated a new endonuclease from FUdR-treated cells, named endonuclease S, that played an important role in FUdR-induced cell death. Cells treated with FUdR showed intracellular acidification before cell death formation. We observed that the endonuclease S in acidic cells may lead the DNA fragmentation. On the other hand, we observed that protease inhibitors (such as TLCK, TPCK, PMSF, p-APMSF, Pefabloc SC and Z-Asp-CH2-DCB) blocked intracellular acidification, DNA fragmentation and FUdR-induced cell death. But the inhibitors did not affect dNTP pool imbalance in the cells. These results suggest that proteases act at the point of downstream of dNTP pool imbalance and upstream of the intracellular acidification.
Nagano
A
A
Faculty of Pharmaceutical Sciences, Okayama University, Japan.
Kakutani
T
T
Matumoto
Y
Y
Ebara
Y
Y
Kanja
K
K
Kankawa
S
S
Wataya
Y
Y
D000818:Animals; D017209:Apoptosis; D016923:Cell Death / Q000187:drug effects*; D002460:Cell Line; D053938:DNA Fragmentation; D015253:Deoxyribonucleases, Type I Site-Specific; D003854:Deoxyribonucleotides / Q000378:metabolism*; D004706:Endodeoxyribonucleases / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism; D005260:Female; D005467:Floxuridine / Q000633:toxicity*; D008325:Mammary Neoplasms, Experimental; D051379:Mice; D011480:Protease Inhibitors / Q000494:pharmacology
D003854:Deoxyribonucleotides; D011480:Protease Inhibitors; D005467:Floxuridine; D004706:Endodeoxyribonucleases; C113086:endonuclease S; D015253:Deoxyribonucleases, Type I Site-Specific; D010450:Endopeptidases