Biomedical Science Letters (대한의생명과학회지)

The Korean Society for Biomedical Laboratory Sciences (대한의생명과학회)
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N-nitroso-N-methylurea and N-nitroso-N-ethylurea Decrease in Nitric Oxide Production in Human Malignant Keratinocytes

  • Moon, Ki-Young (BioMedicinal Chemistry Laboratory, Department of Clinical Pathology, Gwangju Health University)
  • Received : 2018.01.03
  • Accepted : 2018.03.06
  • Published : 2018.03.31
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Abstract

N-nitroso-N-methylurea (NMU) and N-nitroso-N-ethylurea (NEU), direct alkylating chemical mutagens and carcinogens, are shown to be the upregulators of cellular $NF-{\kappa}B$, regulating various genes that mediate tumorigenesis and carcinogenesis. Nitric oxide (NO), a toxic reactive radical gas, has been known to induce programmed cell death or apoptosis in various cells. Therefore, the assessment of NO production was examined to elucidate the possible contribution of NO release to the chemical carcinogenic potency of NMU and NEU in human skin cells. NMU and NEU did not alter the NO production, but they caused a significant downregulation of the NO generation on lipopolysaccharide (LPS)-induced NO production at concentrations ranging from $2{\sim}5{\mu}M$. The degree of downregulation of NO by NMU and NEU decreased up to 15% and 20%, respectively, compared to the control. These results demonstrate that the LPS-inducible keratinocytes NO synthase is involved in modulating carcinogenic potency by NMU and NEU, and the regulation of the cellular $NF-{\kappa}B$ activity by NMU and NEU is negatively correlated with the level of LPS-induced NO production in human skin cells. The findings of this study suggest the hypothesis that NMU and NEU-induced carcinogenesis may be associated with the downregulation of NO production, and the inducible NO may play an important role in NMU and NEU-induced carcinogenicity in human epidermal keratinocytes.

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References

  1. Becherel PA, Chosidow O, Le Goff L, Frances C, Debre P, Mossalayi MD, Arock M. Inducible nitric oxide synthase and proinflammatory cytokine expression by human keratinocytes during acute urticaria. Molecular Medicine. 1997. 3: 686-694.
  2. Bours V, Bentires-Alj M, Hellin AC, Viatour P, Robe P, Delhalle S, Benoit V, Merville MP. Nuclear $factor-{\kappa}B$, cancer, and apoptosis. Biochemical Pharmacology. 2000. 60: 1085-1090. https://doi.org/10.1016/S0006-2952(00)00391-9
  3. Bours V, Dejardin E, Goujon-Letawe F, Merville MP, Castronovo V. The NF-kappa B transcription factor and cancer: high expression of NF-kappa B-and I kappa B-related proteins in tumor cell lines. Biochemical Pharmacology. 1994. 47: 145-149. https://doi.org/10.1016/0006-2952(94)90448-0
  4. Bomsztyk K, Rooney JW, Iwasaki T, Rachie NA, Dower SK, Sibley CH. Evidence that interleukin-1 and phorbol esters activate $NF-{\kappa}B$by different pathways: role of protein kinase C. Cell Regulation. 1991. 2: 329-335. https://doi.org/10.1091/mbc.2.4.329
  5. Brune B, von Knethen A, Sandau KB. Nitric oxide (NO): an effector of apoptosis. Cell Death and Differentiation. 1999. 6: 969-975. https://doi.org/10.1038/sj.cdd.4400582
  6. Heck DE, Laskin DL, Gardner CR, Laskin JD. Epidermal growth factor suppresses nitric oxide and hydrogen peroxide production by keratinocytes. Potential role for nitric oxide in the regulation of wound healing. Journal of Biological Chemistry. 1992. 267: 21277-21280.
  7. Jun CD, Pae HO, Yoo JC, Kwak HJ, Park RK, Chung HT. Cyclic adenosine monophosphate inhibits nitric oxide-induced apoptosis in human leukemic HL-60 cells. Cellular Immunology. 1998. 183: 13-21. https://doi.org/10.1006/cimm.1997.1232
  8. Lee SH, Lee SY, Son DJ, Lee H, Yoo HS, Song S, Oh KW, Han DC, Kwon BM, Hong JT. Inhibitory effect of 2'-hydroxycinnamaldehyde on nitric oxide production through inhibition of $NF-{\kappa}B$ activation in RAW 264.7 cells. Biochemical Pharmacology. 2005. 69: 791-799. https://doi.org/10.1016/j.bcp.2004.11.013
  9. Legrand-Poels S, Zecchinon L, Piret B, Schoonbroodt S, Piette J. Involvement of different transduction pathways in $NF-{\kappa}B$ activation by several inducers. Free Radical Research. 1997. 27: 301-309. https://doi.org/10.3109/10715769709065768
  10. Likhachev AJ, Ivanov MN, Bresil H, Planche-Martel G, Montesano R, Margison GP. Carcinogenicity of single doses of N-nitroso-N-methylurea and N-nitroso-N-ethylurea in syrian golden hamsters and the persistence of alkylated purines in the DNA of various tissues. Cancer Research. 1983. 43: 829-833.
  11. Li F, Zhang J, Arfuso F, Chinnathambi A, Zayed ME, Alharbi SA, Kumar AP, Ahn KS, Sethi G. $NF-{\kappa}B$ in cancer therapy. Archives of Toxicology. 2015. 89: 711-731. https://doi.org/10.1007/s00204-015-1470-4
  12. Messmer UK, Lapetina EG, Brune B. Nitric oxide-induced apoptosis in RAW 264.7 macrophages is antagonized by protein kinase C- and protein kinase A-activating compounds. Molecular Pharmacology. 1995. 47: 757-765.
  13. Moncada S, Palmer RMJ, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacological Reviews. 1991. 43: 109-140.
  14. Moon KY. The chemopreventive effect of retinoids on cellular $NF-{\kappa}B$ activity induced by NMU and NEU in human malignant keratinocytes. Cancer Research and Treatment. 2007. 39: 82-87. https://doi.org/10.4143/crt.2007.39.2.82
  15. Moon KY. N-nitroso-N-methylurea and N-nitroso-N-ethylurea induce upregulation of cellular $NF-{\kappa}B$ activity through protein kinase C-dependent pathway in human malignant keratinocytes. Archives of Pharmacal Research. 2010. 33: 133-139. https://doi.org/10.1007/s12272-010-2235-5
  16. Moon KY. Acrolein, an I-${\kappa}B{\alpha}$-independent downregulation of $NF-{\kappa}B$ activity, causes the decrease in nitric oxide production in human malignant keratinocytes. Archives of Toxicology. 2011. 85: 499-504. https://doi.org/10.1007/s00204-010-0599-4
  17. Moon KY, Hahn BS, Lee J, Kim YS. A cell-based assay system for monitoring $NF-{\kappa}B$ activity in human HaCaT transfectant cells. Analytical Biochemistry. 2001. 292: 17-21. https://doi.org/10.1006/abio.2001.5059
  18. Moon KY, Lee YJ, Kim YS. Upregulation of cellular $NF-{\kappa}B$ activity by alkylating carcinogens in human epidermal kerainocytes. Biological and Pharmaceutical Bulletin. 2003. 26: 1195-1197. https://doi.org/10.1248/bpb.26.1195
  19. Nakamura T, Ushijima T, Ishizaka Y, Nagao M, Nemoto T, Hara M, Ishikawa T. Neu proto-oncogene mutation is specific for the neurofibromas in a N-nitroso-N-ethylurea-induced hamster neurofibromatosis model but not for hamster melanomas and human Schwann cell tumors. Cancer Research. 1994. 54: 976-980.
  20. Nathan C, Xie QW. Nitric oxide synthases: roles, tolls, and controls. Cell. 1994. 78: 915-918. https://doi.org/10.1016/0092-8674(94)90266-6
  21. Perez P, Page A, Jorcano JL. Role of phosphorylated $p50-NF-{\kappa}B$ in the ultraviolet response of mouse skin. Molecular Carcinogenesis. 2000. 27: 272-279. https://doi.org/10.1002/(SICI)1098-2744(200004)27:4<272::AID-MC5>3.0.CO;2-P
  22. Rayet B, Gelinas C. Aberrant rel/nfkb genes and activity in human cancer. Oncogene. 1999. 18: 6938-6947. https://doi.org/10.1038/sj.onc.1203221
  23. Romero-Graillet C, Aberdam E, Clement M, Ortonne JP, Ballotti R. Nitric oxide produced by ultraviolet-irradiated keratinocytes stimulates melanogenesis. Journal of Clinical Investigation. 1997. 99: 635-642. https://doi.org/10.1172/JCI119206
  24. Saliou C, Kitazawa M, McLaughlin L, Yang JP, Lodge JK, Tetsuka T, Iwasaki K, Cillard J, Okamoto T, Packer L. Antioxidants modulate acute solar ultraviolet radiation-induced NF-kappa-B activation in a human keratinocyte cell line. Free Radical Biology and Medicine. 1999. 26: 174-183. https://doi.org/10.1016/S0891-5849(98)00212-3
  25. Scudiero DA, Shoemaker RH, Paull KD, Monks A, Tierney S, Nofziger TH, Currens MJ, Seniff D, Boyd MR. Evaluation of a soluble tetrazolium/formazan assay for cell growth and drug sensitivity in culture using human and other tumor cell lines. Cancer Research. 1988. 48: 4827-4833.
  26. Seo SJ, Choi HG, Chung HJ, Hong CK. Time course of expression of mRNA of inducible nitric oxide synthase and generation of nitric oxide by ultraviolet B in keratinocyte cell lines. British Journal of Dermatology. 2002. 147: 655-662. https://doi.org/10.1046/j.1365-2133.2002.04849.x
  27. Sukumar S, Notario V, Martin-Zanca D, Barbacid M. Induction of mammary carcinomas in rats by nitroso-methylurea involves malignant activation of H-ras-1 locus by single point mutations. Nature. 1983. 306: 658-661. https://doi.org/10.1038/306658a0
  28. Zarbl H, Sukumar S, Arthur AV, Martin-Zanca D, Barbacid M. Direct mutagenesis of Ha-ras-1 oncogenes by N-Nitroso-Nmethylurea during initiation of mammary carcinogenesis in rats. Nature. 1985. 315: 382-385. https://doi.org/10.1038/315382a0