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

Yu-Chen Yang, Han-Yi Elizabeth Chou, Tang-Long Shen, Wei-Jer Chang, Pei-Han Tai, Tsai-Kun Li

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)1129-1140
Number of pages12
JournalAntioxidants and Redox Signaling
Issue number10
Publication statusPublished - 2013
Externally publishedYes


  • 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


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