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 journalArticle

15 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)1129-1140
Number of pages12
JournalAntioxidants and Redox Signaling
Volume18
Issue number10
DOIs
Publication statusPublished - 2013
Externally publishedYes

Fingerprint

Type II DNA Topoisomerase
Mutagenesis
DNA Cleavage
Nitric Oxide
Carcinogenesis
Inflammation
Etoposide
DNA
Skin
Reactive Nitrogen Species
Melanoma
Neoplasms
Isoenzymes
DNA Damage
Reactive Oxygen Species
S-Nitrosoglutathione
Chromosome Breakage
9,10-Dimethyl-1,2-benzanthracene
Phosphorylation
DNA Breaks

Keywords

  • 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

Cite this

Topoisomerase II-mediated DNA cleavage and mutagenesis activated by nitric oxide underlie the inflammation-associated tumorigenesis. / Yang, Yu-Chen; Chou, Han-Yi Elizabeth; Shen, Tang-Long; Chang, Wei-Jer; Tai, Pei-Han; Li, Tsai-Kun.

In: Antioxidants and Redox Signaling, Vol. 18, No. 10, 2013, p. 1129-1140.

Research output: Contribution to journalArticle

Yang, Yu-Chen ; Chou, Han-Yi Elizabeth ; Shen, Tang-Long ; Chang, Wei-Jer ; Tai, Pei-Han ; Li, Tsai-Kun. / Topoisomerase II-mediated DNA cleavage and mutagenesis activated by nitric oxide underlie the inflammation-associated tumorigenesis. In: Antioxidants and Redox Signaling. 2013 ; Vol. 18, No. 10. pp. 1129-1140.
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title = "Topoisomerase II-mediated DNA cleavage and mutagenesis activated by nitric oxide underlie the inflammation-associated tumorigenesis",
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. {\circledC} 2013, Mary Ann Liebert, Inc.",
keywords = "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",
author = "Yu-Chen Yang and Chou, {Han-Yi Elizabeth} and Tang-Long Shen and Wei-Jer Chang and Pei-Han Tai and Tsai-Kun Li",
note = "被引用次數:6 Export Date: 7 April 2016 CODEN: ARSIF 通訊地址: Li, T.-K.; Department and Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan; 電子郵件: tsaikunli@ntu.edu.tw 化學物質/CAS: dimethylbenz[a]anthracene, 43178-07-0; etoposide, 33419-42-0; inducible nitric oxide synthase, 501433-35-8; nitric oxide, 10102-43-9; s nitrosoglutathione, 57564-91-7; 9,10-Dimethyl-1,2-benzanthracene, 57-97-6; DNA Topoisomerases, Type II, 5.99.1.3; Etoposide, 33419-42-0; Nitric Oxide, 10102-43-9; Nitric Oxide Donors; Pyridines; S-Nitrosoglutathione, 57564-91-7; tris(2-pyridylmethyl)amine 商標: vp 16 參考文獻: Andoh, T., Bis(2,6-dioxopiperazines), catalytic inhibitors of DNA topoisomerase II, as molecular probes, cardioprotectors and antitumor drugs (1998) Biochimie, 80, pp. 235-246; Azarova, A.M., Lyu, Y.L., Lin, C.P., Tsai, Y.C., Lau, J.Y., Wang, J.C., Liu, L.F., Roles of DNA topoisomerase II isozymes in chemotherapy and secondary malignancies (2007) Proc Natl Acad Sci USA, 104, pp. 11014-11019; Bartek, J., Hamerlik, P., Lukas, J., On the origin of prostate fusion oncogenes (2010) Nat Genet, 42, pp. 647-648; Bartkova, J., Horejsi, Z., Koed, K., Kramer, A., Tort, F., Zieger, K., Guldberg, P., Bartek, J., DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis (2005) Nature, 434, pp. 864-870; Calmels, S., Hainaut, P., Ohshima, H., Nitric oxide induces conformational and functional modifications of wild-type p53 tumor suppressor protein (1997) Cancer Res, 57, pp. 3365-3369; Castiglione, N., Rinaldo, S., Giardina, G., Stelitano, V., Cutruzzola, F., Nitrite and nitrite reductases: From molecular mechanisms to significance in human health and disease (2012) Antioxid Redox Signal, 17, pp. 684-716; Chazotte-Aubert, L., Hainaut, P., Ohshima, H., Nitric oxide nitrates tyrosine residues of tumor-suppressor p53 protein in MCF-7 cells (2000) Biochem Biophys Res Commun, 267, pp. 609-613; Chazotte-Aubert, L., Oikawa, S., Gilibert, I., Bianchini, F., Kawanishi, S., Ohshima, H., Cytotoxicity and site-specific DNA damage induced by nitroxyl anion (NO(-)) in the presence of hydrogen peroxide. Implications for various pathophysiological conditions (1999) J Biol Chem, 274, pp. 20909-20915; Classen, S., Olland, S., Berger, J.M., Structure of the topoisomerase II ATPase region and its mechanism of inhibition by the chemotherapeutic agent ICRF-187 (2003) Proc Natl Acad Sci USA, 100, pp. 10629-10634; Colotta, F., Allavena, P., Sica, A., Garlanda, C., Mantovani, A., Cancer-related inflammation, the seventh hallmark of cancer: Links to genetic instability (2009) Carcinogenesis, 30, pp. 1073-1081; D'Antuono, M., Biagini, G., Tancredi, V., Avoli, M., Electrophysiology of regular firing cells in the rat perirhinal cortex (2001) Hippocampus, 11, pp. 662-672; Daroui, P., Desai, S.D., Li, T.K., Liu, A.A., Liu, L.F., Hydrogen peroxide induces topoisomerase I-mediated DNA damage and cell death (2004) J Biol Chem, 279, pp. 14587-14594; Fan, J.R., Peng, A.L., Chen, H.C., Lo, S.C., Huang, T.H., Li, T.K., Cellular processing pathways contribute to the activation of etoposide-induced DNA damage responses (2008) DNA Repair (Amst), 7, pp. 452-463; Feng, C.W., Wang, L.D., Jiao, L.H., Liu, B., Zheng, S., Xie, X.J., Expression of p53, inducible nitric oxide synthase and vascular endothelial growth factor in gastric precancerous and cancerous lesions: Correlation with clinical features (2002) BMC Cancer, 2, p. 8; Gorgoulis, V.G., Vassiliou, L.V., Karakaidos, P., Zacharatos, P., Kotsinas, A., Liloglou, T., Venere, M., Halazonetis, T.D., Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions (2005) Nature, 434, pp. 907-913; Gupta, S.C., Hevia, D., Patchva, S., Park, B., Koh, W., Aggarwal, B.B., Upsides and downsides of reactive oxygen species for cancer: The roles of reactive oxygen species in tumorigenesis, prevention, and therapy (2012) Antioxid Redox Signal, 16, pp. 1295-1322; Haffner, M.C., Aryee, M.J., Toubaji, A., Esopi, D.M., Albadine, R., Gurel, B., Isaacs, W.B., Yegnasubramanian, S., Androgen-induced TOP2B-mediated double-strand breaks and prostate cancer gene rearrangements (2010) Nat Genet, 42, pp. 668-675; Hanahan, D., Weinberg, R.A., Hallmarks of cancer: The next generation (2011) Cell, 144, pp. 646-674; Harker, W.G., Slade, D.L., Parr, R.L., Holguin, M.H., Selective use of an alternative stop codon and polyadenylation signal within intron sequences leads to a truncated topoisomerase II alpha messenger RNA and protein in human HL-60 leukemia cells selected for resistance to mitoxantrone (1995) Cancer Res, 55, pp. 4962-4971; Hellmann, K., Overview and historical development of dexrazoxane (1998) Semin Oncol, 25, pp. 48-54; Hofseth, L.J., Saito, S., Hussain, S.P., Espey, M.G., Miranda, K.M., Araki, Y., Jhappan, C., Harris, C.C., Nitric oxide-induced cellular stress and p53 activation in chronic inflammation (2003) Proc Natl Acad Sci USA, 100, pp. 143-148; Huang, T.H., Chen, H.C., Chou, S.M., Yang, Y.C., Fan, J.R., Li, T.K., Cellular processing determinants for the activation of damage signals in response to topoisomerase I-linked DNA breakage (2010) Cell Res, 20, pp. 1060-1075; Li, T.K., Chen, A.Y., Yu, C., Mao, Y., Wang, H., Liu, L.F., Activation of topoisomerase II-mediated excision of chromosomal DNA loops during oxidative stress (1999) Genes Dev, 13, pp. 1553-1560; Li, T.K., Houghton, P.J., Desai, S.D., Daroui, P., Liu, A.A., Hars, E.S., Ruchelman, A.L., Liu, L.F., Characterization of ARC-111 as a novel topoisomerase I-targeting anticancer drug (2003) Cancer Res, 63, pp. 8400-8407; Li, T.K., Liu, L.F., Tumor cell death induced by topoisomerase-targeting drugs (2001) Annu Rev Pharmacol Toxicol, 41, pp. 53-77; Lotan, T.L., Gupta, N.S., Wang, W., Toubaji, A., Haffner, M.C., Chaux, A., Hicks, J.L., Netto, G.J., ERG gene rearrangements are common in prostatic small cell carcinomas (2011) Mod Pathol, 24, pp. 820-828; Lyu, Y.L., Kerrigan, J.E., Lin, C.P., Azarova, A.M., Tsai, Y.C., Ban, Y., Liu, L.F., Topoisomerase IIbeta mediated DNA doublestrand breaks: Implications in doxorubicin cardiotoxicity and prevention by dexrazoxane (2007) Cancer Res, 67, pp. 8839-8846; Moncada, S., Palmer, R.M., Higgs, E.A., Nitric oxide: Physiology, pathophysiology, and pharmacology (1991) Pharmacol Rev, 43, pp. 109-142; Montecucco, A., Biamonti, G., Cellular response to etoposide treatment (2007) Cancer Lett, 252, pp. 9-18; Mosser, D.M., Edwards, J.P., Exploring the full spectrum of macrophage activation (2008) Nat Rev Immunol, 8, pp. 958-969; Nitiss, J.L., DNA topoisomerase II and its growing repertoire of biological functions (2009) Nat Rev Cancer, 9, pp. 327-337; Nitiss, J.L., Targeting DNA topoisomerase II in cancer chemotherapy (2009) Nat Rev Cancer, 9, pp. 338-350; Palanisamy, N., Ateeq, B., Kalyana-Sundaram, S., Pflueger, D., Ramnarayanan, K., Shankar, S., Han, B., Chinnaiyan, A.M., Rearrangements of the RAF kinase pathway in prostate cancer, gastric cancer and melanoma (2010) Nat Med, 16, pp. 793-798; Robinson, D.R., Kalyana-Sundaram, S., Wu, Y.M., Shankar, S., Cao, X., Ateeq, B., Asangani, I.A., Chinnaiyan, A.M., Functionally recurrent rearrangements of the MAST kinase and Notch gene families in breast cancer (2011) Nat Med, 17, pp. 1646-1651; Rowley, J.D., The critical role of chromosome translocations in human leukemias (1998) Annu Rev Genet, 32, pp. 495-519; Salk, J.J., Salipante, S.J., Risques, R.A., Crispin, D.A., Li, L., Bronner, M.P., Brentnall, T.A., Loeb, L.A., Clonal expansions in ulcerative colitis identify patients with neoplasia (2009) Proc Natl Acad Sci USA, 106, pp. 20871-20876; Solovyan, V.T., Bezvenyuk, Z.A., Salminen, A., Austin, C.A., Courtney, M.J., The role of topoisomerase II in the excision of DNA loop domains during apoptosis (2002) J Biol Chem, 277, pp. 21458-21467; Wang, H., Mao, Y., Chen, A.Y., Zhou, N., Lavoie, E.J., Liu, L.F., Stimulation of topoisomerase II-mediated DNA damage via a mechanism involving protein thiolation (2001) Biochemistry, 40, pp. 3316-3323; Wu, C.C., Li, T.K., Farh, L., Lin, L.Y., Lin, T.S., Yu, Y.J., Yen, T.J., Chan, N.L., Structural basis of type II topoisomerase inhibition by the anticancer drug etoposide (2011) Science, 333, pp. 459-462; Xiao, H., Li, T.K., Yang, J.M., Liu, L.F., Acidic pH induces topoisomerase II-mediated DNA damage (2003) Proc Natl Acad Sci USA, 100, pp. 5205-5210; Yamazaki, F., Okamoto, H., Matsumura, Y., Tanaka, K., Kunisada, T., Horio, T., Development of a new mouse model (xeroderma pigmentosum a-deficient, stem cell factor-transgenic) of ultraviolet B-induced melanoma (2005) J Invest Dermatol, 125, pp. 521-525; Zhang, Y., Strissel, P., Strick, R., Chen, J., Nucifora, G., Le Beau, M.M., Larson, R.A., Rowley, J.D., Genomic DNA breakpoints in AML1/RUNX1 and ETO cluster with topoisomerase II DNA cleavage and DNase i hypersensitive sites in t(8;21) leukemia (2002) Proc Natl Acad Sci USA, 99, pp. 3070-3075; Zhou, N., Xiao, H., Li, T.K., Nur, E.K.A., Liu, L.F., DNA damage-mediated apoptosis induced by selenium compounds (2003) J Biol Chem, 278, pp. 29532-29537",
year = "2013",
doi = "10.1089/ars.2012.4620",
language = "English",
volume = "18",
pages = "1129--1140",
journal = "Antioxidants and Redox Signaling",
issn = "1523-0864",
publisher = "Mary Ann Liebert Inc.",
number = "10",

}

TY - JOUR

T1 - Topoisomerase II-mediated DNA cleavage and mutagenesis activated by nitric oxide underlie the inflammation-associated tumorigenesis

AU - Yang, Yu-Chen

AU - Chou, Han-Yi Elizabeth

AU - Shen, Tang-Long

AU - Chang, Wei-Jer

AU - Tai, Pei-Han

AU - Li, Tsai-Kun

N1 - 被引用次數:6 Export Date: 7 April 2016 CODEN: ARSIF 通訊地址: Li, T.-K.; Department and Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan; 電子郵件: tsaikunli@ntu.edu.tw 化學物質/CAS: dimethylbenz[a]anthracene, 43178-07-0; etoposide, 33419-42-0; inducible nitric oxide synthase, 501433-35-8; nitric oxide, 10102-43-9; s nitrosoglutathione, 57564-91-7; 9,10-Dimethyl-1,2-benzanthracene, 57-97-6; DNA Topoisomerases, Type II, 5.99.1.3; Etoposide, 33419-42-0; Nitric Oxide, 10102-43-9; Nitric Oxide Donors; Pyridines; S-Nitrosoglutathione, 57564-91-7; tris(2-pyridylmethyl)amine 商標: vp 16 參考文獻: Andoh, T., Bis(2,6-dioxopiperazines), catalytic inhibitors of DNA topoisomerase II, as molecular probes, cardioprotectors and antitumor drugs (1998) Biochimie, 80, pp. 235-246; Azarova, A.M., Lyu, Y.L., Lin, C.P., Tsai, Y.C., Lau, J.Y., Wang, J.C., Liu, L.F., Roles of DNA topoisomerase II isozymes in chemotherapy and secondary malignancies (2007) Proc Natl Acad Sci USA, 104, pp. 11014-11019; Bartek, J., Hamerlik, P., Lukas, J., On the origin of prostate fusion oncogenes (2010) Nat Genet, 42, pp. 647-648; Bartkova, J., Horejsi, Z., Koed, K., Kramer, A., Tort, F., Zieger, K., Guldberg, P., Bartek, J., DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis (2005) Nature, 434, pp. 864-870; Calmels, S., Hainaut, P., Ohshima, H., Nitric oxide induces conformational and functional modifications of wild-type p53 tumor suppressor protein (1997) Cancer Res, 57, pp. 3365-3369; Castiglione, N., Rinaldo, S., Giardina, G., Stelitano, V., Cutruzzola, F., Nitrite and nitrite reductases: From molecular mechanisms to significance in human health and disease (2012) Antioxid Redox Signal, 17, pp. 684-716; Chazotte-Aubert, L., Hainaut, P., Ohshima, H., Nitric oxide nitrates tyrosine residues of tumor-suppressor p53 protein in MCF-7 cells (2000) Biochem Biophys Res Commun, 267, pp. 609-613; Chazotte-Aubert, L., Oikawa, S., Gilibert, I., Bianchini, F., Kawanishi, S., Ohshima, H., Cytotoxicity and site-specific DNA damage induced by nitroxyl anion (NO(-)) in the presence of hydrogen peroxide. Implications for various pathophysiological conditions (1999) J Biol Chem, 274, pp. 20909-20915; Classen, S., Olland, S., Berger, J.M., Structure of the topoisomerase II ATPase region and its mechanism of inhibition by the chemotherapeutic agent ICRF-187 (2003) Proc Natl Acad Sci USA, 100, pp. 10629-10634; Colotta, F., Allavena, P., Sica, A., Garlanda, C., Mantovani, A., Cancer-related inflammation, the seventh hallmark of cancer: Links to genetic instability (2009) Carcinogenesis, 30, pp. 1073-1081; D'Antuono, M., Biagini, G., Tancredi, V., Avoli, M., Electrophysiology of regular firing cells in the rat perirhinal cortex (2001) Hippocampus, 11, pp. 662-672; Daroui, P., Desai, S.D., Li, T.K., Liu, A.A., Liu, L.F., Hydrogen peroxide induces topoisomerase I-mediated DNA damage and cell death (2004) J Biol Chem, 279, pp. 14587-14594; Fan, J.R., Peng, A.L., Chen, H.C., Lo, S.C., Huang, T.H., Li, T.K., Cellular processing pathways contribute to the activation of etoposide-induced DNA damage responses (2008) DNA Repair (Amst), 7, pp. 452-463; Feng, C.W., Wang, L.D., Jiao, L.H., Liu, B., Zheng, S., Xie, X.J., Expression of p53, inducible nitric oxide synthase and vascular endothelial growth factor in gastric precancerous and cancerous lesions: Correlation with clinical features (2002) BMC Cancer, 2, p. 8; Gorgoulis, V.G., Vassiliou, L.V., Karakaidos, P., Zacharatos, P., Kotsinas, A., Liloglou, T., Venere, M., Halazonetis, T.D., Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions (2005) Nature, 434, pp. 907-913; Gupta, S.C., Hevia, D., Patchva, S., Park, B., Koh, W., Aggarwal, B.B., Upsides and downsides of reactive oxygen species for cancer: The roles of reactive oxygen species in tumorigenesis, prevention, and therapy (2012) Antioxid Redox Signal, 16, pp. 1295-1322; Haffner, M.C., Aryee, M.J., Toubaji, A., Esopi, D.M., Albadine, R., Gurel, B., Isaacs, W.B., Yegnasubramanian, S., Androgen-induced TOP2B-mediated double-strand breaks and prostate cancer gene rearrangements (2010) Nat Genet, 42, pp. 668-675; Hanahan, D., Weinberg, R.A., Hallmarks of cancer: The next generation (2011) Cell, 144, pp. 646-674; Harker, W.G., Slade, D.L., Parr, R.L., Holguin, M.H., Selective use of an alternative stop codon and polyadenylation signal within intron sequences leads to a truncated topoisomerase II alpha messenger RNA and protein in human HL-60 leukemia cells selected for resistance to mitoxantrone (1995) Cancer Res, 55, pp. 4962-4971; Hellmann, K., Overview and historical development of dexrazoxane (1998) Semin Oncol, 25, pp. 48-54; Hofseth, L.J., Saito, S., Hussain, S.P., Espey, M.G., Miranda, K.M., Araki, Y., Jhappan, C., Harris, C.C., Nitric oxide-induced cellular stress and p53 activation in chronic inflammation (2003) Proc Natl Acad Sci USA, 100, pp. 143-148; Huang, T.H., Chen, H.C., Chou, S.M., Yang, Y.C., Fan, J.R., Li, T.K., Cellular processing determinants for the activation of damage signals in response to topoisomerase I-linked DNA breakage (2010) Cell Res, 20, pp. 1060-1075; Li, T.K., Chen, A.Y., Yu, C., Mao, Y., Wang, H., Liu, L.F., Activation of topoisomerase II-mediated excision of chromosomal DNA loops during oxidative stress (1999) Genes Dev, 13, pp. 1553-1560; Li, T.K., Houghton, P.J., Desai, S.D., Daroui, P., Liu, A.A., Hars, E.S., Ruchelman, A.L., Liu, L.F., Characterization of ARC-111 as a novel topoisomerase I-targeting anticancer drug (2003) Cancer Res, 63, pp. 8400-8407; Li, T.K., Liu, L.F., Tumor cell death induced by topoisomerase-targeting drugs (2001) Annu Rev Pharmacol Toxicol, 41, pp. 53-77; Lotan, T.L., Gupta, N.S., Wang, W., Toubaji, A., Haffner, M.C., Chaux, A., Hicks, J.L., Netto, G.J., ERG gene rearrangements are common in prostatic small cell carcinomas (2011) Mod Pathol, 24, pp. 820-828; Lyu, Y.L., Kerrigan, J.E., Lin, C.P., Azarova, A.M., Tsai, Y.C., Ban, Y., Liu, L.F., Topoisomerase IIbeta mediated DNA doublestrand breaks: Implications in doxorubicin cardiotoxicity and prevention by dexrazoxane (2007) Cancer Res, 67, pp. 8839-8846; Moncada, S., Palmer, R.M., Higgs, E.A., Nitric oxide: Physiology, pathophysiology, and pharmacology (1991) Pharmacol Rev, 43, pp. 109-142; Montecucco, A., Biamonti, G., Cellular response to etoposide treatment (2007) Cancer Lett, 252, pp. 9-18; Mosser, D.M., Edwards, J.P., Exploring the full spectrum of macrophage activation (2008) Nat Rev Immunol, 8, pp. 958-969; Nitiss, J.L., DNA topoisomerase II and its growing repertoire of biological functions (2009) Nat Rev Cancer, 9, pp. 327-337; Nitiss, J.L., Targeting DNA topoisomerase II in cancer chemotherapy (2009) Nat Rev Cancer, 9, pp. 338-350; Palanisamy, N., Ateeq, B., Kalyana-Sundaram, S., Pflueger, D., Ramnarayanan, K., Shankar, S., Han, B., Chinnaiyan, A.M., Rearrangements of the RAF kinase pathway in prostate cancer, gastric cancer and melanoma (2010) Nat Med, 16, pp. 793-798; Robinson, D.R., Kalyana-Sundaram, S., Wu, Y.M., Shankar, S., Cao, X., Ateeq, B., Asangani, I.A., Chinnaiyan, A.M., Functionally recurrent rearrangements of the MAST kinase and Notch gene families in breast cancer (2011) Nat Med, 17, pp. 1646-1651; Rowley, J.D., The critical role of chromosome translocations in human leukemias (1998) Annu Rev Genet, 32, pp. 495-519; Salk, J.J., Salipante, S.J., Risques, R.A., Crispin, D.A., Li, L., Bronner, M.P., Brentnall, T.A., Loeb, L.A., Clonal expansions in ulcerative colitis identify patients with neoplasia (2009) Proc Natl Acad Sci USA, 106, pp. 20871-20876; 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PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

KW - dimethylbenz[a]anthracene

KW - DNA topoisomerase (ATP hydrolysing)

KW - etoposide

KW - histone H2AX

KW - inducible nitric oxide synthase

KW - nitric oxide

KW - protein p53

KW - s nitrosoglutathione

KW - animal experiment

KW - article

KW - carcinogenesis

KW - controlled study

KW - cytotoxicity

KW - DNA cleavage

KW - DNA sequence

KW - DNA strand breakage

KW - enzyme phosphorylation

KW - inflammation

KW - macrophage

KW - melanoma

KW - mouse

KW - mutagenesis

KW - nonhuman

KW - phenotype

KW - priority journal

KW - 9,10-Dimethyl-1,2-benzanthracene

KW - Animals

KW - Cell Line

KW - Cell Transformation, Neoplastic

KW - Coculture Techniques

KW - DNA Cleavage

KW - DNA Topoisomerases, Type II

KW - Etoposide

KW - HCT116 Cells

KW - HL-60 Cells

KW - Humans

KW - Inflammation

KW - Mice

KW - Mice, Knockout

KW - Mutagenesis

KW - Nitric Oxide

KW - Nitric Oxide Donors

KW - Pyridines

KW - S-Nitrosoglutathione

U2 - 10.1089/ars.2012.4620

DO - 10.1089/ars.2012.4620

M3 - Article

VL - 18

SP - 1129

EP - 1140

JO - Antioxidants and Redox Signaling

JF - Antioxidants and Redox Signaling

SN - 1523-0864

IS - 10

ER -