8-Hydroxydeoxyguanosine causes death of human leukemia cells deficient in 8-oxoguanine glycosylase 1 activity by inducing apoptosis

Jin Won Hyun, Yoon Chul Jung, Hyun Sook Kim, Eun Young Choi, Ja Eun Kim, Byung Hak Yoon, Sun Hee Yoon, Yun Sil Lee, Jinhee Choi, Ho Jin You, Myung Hee Chung

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Our previous study showed that KG-1, a human acute leukemia cell line, has mutational loss of 8-oxoguanine (8-hydroxyguanine; oh8Gua) glycosylase 1 (OGG1) activity and that its viability is severely affected by 8-hydroxydeoxyguanosine (8-oxodeoxyguanosine; oh8dG). In the present study, the nature of the killing action of oh8dG on KG-1 was investigated. Signs observed in oh8dG-treated KG-1 cells indicated that death was due to apoptosis, as demonstrated by: increased sub-G1 hypodiploid (apoptotic) cells, DNA fragmentation, and apoptotic body formation; loss of mitochondrial transmembrane potential, the release of cytochrome c from mitochondria into the cytosol, and the down-regulation of bcl-2; and the activation of caspases 8, 9, and 3, and the efficient inhibition of the apoptotic process by caspases inhibitors. This apoptosis appears not to be associated with Fas/Fas ligand because the expressions of these proteins were unchanged. Apoptotic KG-1 cells showed a high concentration of oh8Gua in DNA. Moreover, the increased concentration of oh8Gua in DNA, and the apoptotic process were not suppressed by the antioxidant, N-acetylcysteine, and thus the process is independent of reactive oxygen species. Of the 18 cancer cell lines treated with oh8dG, 3 cell lines (H9, CEM-CM3, and Molt-4) were found to be committed to apoptosis, and all of these showed very low OGG1 activity and a marked increase in the concentration of oh8Gua in DNA. These observations indicate that in addition to its mutagenic action, oh8Gua in DNA disturbs cell viability by inducing apoptosis.

Original languageEnglish
Pages (from-to)290-299
Number of pages10
JournalMolecular Cancer Research
Volume1
Issue number4
StatePublished - 1 Feb 2003

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