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  4. Topoisomerase II-mediated DNA cleavage and mutagenesis activated by nitric oxide underlie the inflammation-associated tumorigenesis
 
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Topoisomerase II-mediated DNA cleavage and mutagenesis activated by nitric oxide underlie the inflammation-associated tumorigenesis

Journal
Antioxidants and Redox Signaling
Journal Volume
18
Journal Issue
10
Pages
1129-1140
Date Issued
2013
Author(s)
Yang Y.-C.
HAN-YI E. CHOU  
Shen T.-L.
Chang W.-J.
Tai P.-H.
TSAI-KUN LI  
DOI
10.1089/ars.2012.4620
URI
https://www.scopus.com/inward/record.uri?eid=2-s2.0-84874059703&doi=10.1089%2fars.2012.4620&partnerID=40&md5=61e87fecef36ebea8ab17c804dba077c
https://scholars.lib.ntu.edu.tw/handle/123456789/597270
Abstract
Aims: Both cancer-suppressing and cancer-promoting properties of reactive nitrogen and oxygen species (RNOS) have been suggested to play a role in tumor pathology, particularly those activities associated with chronic inflammation. Here, we address the impact of nitric oxide (NO) on the induction of DNA damage and genome instability with a specific focus on the involvement of topoisomerase II (TOP2). We also investigate the contribution of NO to the formation of skin melanoma in mice. Results: Similar to the TOP2-targeting drug, etoposide (VP-16), the NO-donor, S-nitrosoglutathione (GSNO), induces skin melanomas formation in 7,12-dimethyl-benz[a]anthracene (DMBA)-initiated mice. To explore the mechanism(s) underlying this NO-induced tumorigenesis, we use a co-culture model system to demonstrate that inflamed macrophages with inducible NO synthase (iNOS) expression cause γ-H2AX activation, p53 phosphorylation, and chromosome DNA breaks in the target cells. Inhibitor experiments revealed that NO and TOP2 isozymes are responsible for the above described cellular phenotypes. Notably, NO, unlike VP-16, preferentially induces the formation of TOP2β cleavable complexes (TOP2βcc) in cells. Moreover, GSNO induced TOP2-dependent DNA sequence rearrangements and cytotoxicity. Furthermore, the incidences of GSNO-and VP-16-induced skin melanomas were also observed to be lower in the skin-specific top2β-knockout mice. Our results suggest that TOP2 isozymes contribute to NO-induced mutagenesis and subsequent cancer development during chronic inflammation. Innovation and Conclusions: We provide the first experimental evidence for the functional role of TOP2 in NO-caused DNA damage, mutagenesis, and carcinogenesis. Notably, these studies contribute to our molecular understanding of the cancer-promoting actions of RNOS during chronic inflammation. Antioxid. Redox Signal. 18, 1129-1140. ? 2013, Mary Ann Liebert, Inc.
SDGs

[SDGs]SDG3

Other Subjects
dimethylbenz[a]anthracene; DNA topoisomerase (ATP hydrolysing); etoposide; histone H2AX; inducible nitric oxide synthase; nitric oxide; protein p53; s nitrosoglutathione; animal experiment; article; carcinogenesis; controlled study; cytotoxicity; DNA cleavage; DNA sequence; DNA strand breakage; enzyme phosphorylation; inflammation; macrophage; melanoma; mouse; mutagenesis; nonhuman; phenotype; priority journal; 9,10-Dimethyl-1,2-benzanthracene; Animals; Cell Line; Cell Transformation, Neoplastic; Coculture Techniques; DNA Cleavage; DNA Topoisomerases, Type II; Etoposide; HCT116 Cells; HL-60 Cells; Humans; Inflammation; Mice; Mice, Knockout; Mutagenesis; Nitric Oxide; Nitric Oxide Donors; Pyridines; S-Nitrosoglutathione
Type
journal article

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