title: DNA damage-mediated apoptosis induced by selenium compounds.
abstract: Selenium (Se) compounds, which are the most extensively studied cancer chemopreventive agents, induce apoptotic death of tumor cells. In the current study, we show that selenite-induced apoptosis involves DNA damage. We showed that selenite-induced apoptosis as evidenced by cleavage of poly(ADP-ribose) polymerase was reduced in NIH 3T3 cells treated with ATM small interfering RNA, suggesting the involvement of the DNA damage regulator ATM. Consistent with ATM/ATR involvement, selenite was also shown to stimulate Ser-139 phosphorylation of the ATM/ATR substrate H2AX. Selenite-induced apoptosis was shown to involve DNA topoisomerase II (Top II) as selenite-induced apoptosis was reduced in Top II-deficient HL-60/MX2 cells and in HL-60 cells co-treated with the Top II catalytic inhibitor ICRF-193. Using purified human recombinant Top II, selenite was shown to induce reversible Top II cleavage complexes in vitro. In the aggregate, these results suggest that selenite-induced apoptosis, which involves ATM/ATR and Top II, is likely to be because of DNA damage.
authors.affiliation: Department of Pharmacology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA.
authors.forename: Nai
authors.initials: N
authors.lastname: Zhou
authors.forename: Hai
authors.initials: H
authors.lastname: Xiao
authors.forename: Tsai-Kun
authors.initials: TK
authors.lastname: Li
authors.forename: Alam
authors.initials: A
authors.lastname: Nur-E-Kamal
authors.forename: Leroy F
authors.initials: LF
authors.lastname: Liu
mesh_terms: D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis; D020552:Comet Assay; D004249:DNA Damage; D053938:DNA Fragmentation; D054659:Diketopiperazines; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000378:metabolism; D018922:HL-60 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry; D012643:Selenium / Q000494:pharmacology*; D012694:Serine / Q000737:chemistry
chemical_list: D054659:Diketopiperazines; D006657:Histones; D010879:Piperazines; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; C070899:4,4'-(1,2-dimethyl-1,2-ethanediyl)bis-2,6-piperazinedione; D012694:Serine; D011065:Poly(ADP-ribose) Polymerases; D005978:Glutathione; D012643:Selenium