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5-Phenylselenyl- and 5-methylselenyl-methyl-2'-deoxyuridine induce oxidative stress, DNA damage, and caspase-2-dependent apoptosis in cancer cells

Authors
 Byeong Mo Kim  ;  Ambadas B. Rode  ;  Eun Jong Han  ;  In Seok Hong  ;  Sung Hee Hong 
Citation
 Apoptosis, Vol.17(2) : 200-216, 2012 
Journal Title
 Apoptosis 
ISSN
 1360-8185 
Issue Date
2012
MeSH
Apoptosis/drug effects* ; Apoptosis/genetics ; Caspase 2/genetics ; Caspase 2/metabolism* ; Caspase 3/genetics ; Caspase 3/metabolism* ; Caspase Inhibitors ; Cell Line, Tumor ; DNA Damage/drug effects ; Deoxyuridine/administration & dosage ; Deoxyuridine/analogs & derivatives* ; Enzyme Activation/drug effects ; Humans ; Neoplasms/metabolism* ; Oligopeptides/administration & dosage ; Organoselenium Compounds/administration & dosage* ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Signal Transduction
Abstract
In the present study, we investigated the signaling pathways implicated in the induction of apoptosis by two modified nucleosides, 5-phenylselenyl-methyl-2'-deoxyuridine (PhSe-T) and 5-methylselenyl-methyl-2'-deoxyuridine (MeSe-T), using human cancer cell lines. The induction of apoptosis was associated with proteolytic activation of caspase-3 and -9, PARP cleavage, and decreased levels of IAP family members, including c-IAP-1 and c-IAP-2, but had no effect on XIAP and survivin. PhSe-T and MeSe-T also enhanced the activities of caspase-2 and -8, Bid cleavage, and the conformational activation of Bax. Additionally, nucleoside derivative-induced apoptosis was inhibited by the selective inhibitors of caspase-2, -3, -8, and -9 and also by si-RNAs against caspase-2, -3, -8, and -9; however, inhibition of caspase-2 and -3 was more effective at preventing apoptosis than inhibition of caspase-8 and -9. Moreover, the inhibition of caspase-2 activation by the pharmacological inhibitor z-VDVAD-fmk or by the knockdown of protein expression using siRNA suppressed nucleoside derivative-induced caspase-3 activation, but not vice versa. PhSe-T and MeSe-T also induced a Δψ(m) loss via a CsA-insensitive mechanism, ROS production, and DNA damage, including strand breaks. Moreover, ROS scavengers such as NAC, tiron, and quercetin inhibited nucleoside derivative-induced ROS generation and apoptosis by blocking the sequential activation of caspase-2 and -3, indicating the role of ROS in caspase-2-mediated apoptosis. Taken together, these results indicate that caspase-2 acts upstream of caspase-3 and that caspase-2 functions in response to DNA damage in both PhSe-T- and MeSe-T-induced apoptosis. Our results also suggest that ROS are critical regulators of the sequential activation of caspase-2 and -3 in nucleoside derivative-treated cancer cells.
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/158298
DOI
10.1007/s10495-011-0665-2
Appears in Collections:
1. Journal Papers (연구논문) > 5. Research Institutes (연구소) > Yonsei Integrative Research Institute for Cerebral & Cardiovascular Disease (뇌심혈관질환융합연구사업단)
Yonsei Authors
김병모(Kim, Byeong Mo)
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Full Text
https://link.springer.com/article/10.1007/s10495-011-0665-2
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