Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
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4-(N-Methyl-N-nitrosamino)-1(3-pyridyl)-1-butanone(NNK) Restored the Cap-dependent Protein Translation Blocked by Rapamycin

  • Kim Jun-Sung (Laboratory of Toxicology, College of Veterinary Medicine, and School of Agricultural Biotechnology, Seoul National University) ;
  • Park Jin Hong (Laboratory of Toxicology, College of Veterinary Medicine, and School of Agricultural Biotechnology, Seoul National University) ;
  • Park Sung-Jin (Laboratory of Toxicology, College of Veterinary Medicine, and School of Agricultural Biotechnology, Seoul National University) ;
  • Kim Hyun Woo (Laboratory of Toxicology, College of Veterinary Medicine, and School of Agricultural Biotechnology, Seoul National University) ;
  • Hua Jin (Laboratory of Toxicology, College of Veterinary Medicine, and School of Agricultural Biotechnology, Seoul National University) ;
  • Cho Hyun Sun (Laboratory of Toxicology, College of Veterinary Medicine, and School of Agricultural Biotechnology, Seoul National University) ;
  • Hwang Soon Kyung (Laboratory of Toxicology, College of Veterinary Medicine, and School of Agricultural Biotechnology, Seoul National University) ;
  • Chang Seung Hee (Laboratory of Toxicology, College of Veterinary Medicine, and School of Agricultural Biotechnology, Seoul National University) ;
  • Tehrani Arash Minai (Laboratory of Toxicology, College of Veterinary Medicine, and School of Agricultural Biotechnology, Seoul National University) ;
  • Cho Myung Haing (Laboratory of Toxicology, College of Veterinary Medicine, and School of Agricultural Biotechnology, Seoul National University)
  • Published : 2005.12.01
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Abstract

Eukaryotic initiation factor 4E (elF4E) is a key element for cap-dependent protein translation controlled by affinity between elF4E and 4E-binding protein 1 (4E-BP1). Rapamycin can also affect protein translation by regulating 4E-BP1 phosphorylation. Tobacco-specific nitrosamine, 4(N-methyl-N-nitrosamino )-1-(3-pyridyl)-1-butanone (NNK) is a strong lung carcinogen, but its precise lung cancer induction mechanism remains unknown. Relative roles of cap-dependent and -independent protein translation in terms of NNK-induced lung carcinogenesis were elucidated using normal human bronchial epithelial cells. NNK concentrations applied in this study did not decrease cell viability. Addition of NNK restored rapamycin-induced decrease of protein synthesis and rapamycin-induced phosphorylation of 4E-BP1, and increased expression levels of mTOR, ERK1/2, p70S6K, and Raf-1 in a concentration-dependent manner. NNK also caused perturbation of normal cell cycle progression. Taken together, NNK might cause toxicity through the combination of restoration of 4E-BP1 phosphorylation and increase of elF4E as well as mTOR protein expression, interruption of Raf1/ERK as well as the cyclin G-associated p53 network. Our data could be applied towards elucidation of the molecular basis for lung cancer treatment.

Keywords

References

  1. Agarwal, C., Singh, R.P., Dhanalakshmi, S., Tyagi, A.K., Teck-lenburg, M., Sclafani, R.A. and Agarwal, R. (2003): Silibinin upregulates the expression of cyclin-dependent kinase inhibitors and causes cell cycle arrest and apoptosis in human colon carcinoma HT-29 cells. Oncogene, 22, 8271-8282 https://doi.org/10.1038/sj.onc.1207158
  2. Agopyan, N., Bhatti, T., Yu, S. and Simon, S.A. (2003): Vanilloid receptor activation by 2- and 10-microm particles induces responses leading to apoptosis in human airway epithelial cells. Toxicol. Appl. Pharmacol., 192, 21-35 https://doi.org/10.1016/S0041-008X(03)00259-X
  3. Bhandari, B.K., Feliers, D., Duraisamy, S., Stewart, J.L., Gingras, A.C., Abboud, H.E., Choudhury, G.G., Sonenberg, N. and Kasinath, B.S. (2001): Insulin regulation of protein translation repressor 4E-BP1, and elF4E-binding protein, in renal epithelial cells. Kidney International, 59, 866-875 https://doi.org/10.1046/j.1523-1755.2001.059003866.x
  4. Brown, E.J., Albers, M.W., Shin, T.B., Ichikawa, K., Keith, C.T., Lane, W.S. and Schreiber, S.L. (1994): A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature, 369, 756-758 https://doi.org/10.1038/369756a0
  5. Chappell, S.A., LeQuesne, J.P., Paulin, F.E., de School meester, M.L., Stoneley, M., Soutar, R.L., Ralston, S.H., Helfrich, M.H. and Willis, A.E. (2002): A mutation in the c-myc-IRES leads to enhanced internal ribosome entry in multiple myeloma: a novel mechanism of oncogene de-regulation. Oncogene, 19, 4437-4440 https://doi.org/10.1038/sj.onc.1203791
  6. Clark, J.A., Black, A.R., Leontieva, O.V., Frey, M.R., Pysz, M.A., Kunneva, L., Woloazynska-Read, A., Roy, D. and Black, J.D. (2003): Involvement of the ERK signaling cascade in protein kinase C-mediated cell cycle arrest in intestinal epithelial cells. J. Biol. Chem., in press
  7. Coldwell, M.J., Mitchell, S.A., Stoneley, M., MacFarlane, M. and Willis, A.E. (2000): Initiation of Apaf-1 translation by internal ribosome entry. Oncogene, 19, 899-905 https://doi.org/10.1038/sj.onc.1203407
  8. Davies, C.C., Mason, J., Wakelam, M.J., Young, L.S. and Eliopoulos A.G. (2003): Inhibition of PI3K and ERK MAPKregulated protein synthesis reveals the pro-apoptotic properties of CD40 ligation in carcinoma cells. J. Biol. Chem., in press https://doi.org/10.1074/jbc.M303820200
  9. Dubois, S., Shou, W., Haneline, L.S., Fleisher, S., Waldmann, T.A. and Muller, J.R. (2003): Distinct pathways involving the FK506-binding proteins 12 and 12.6 underlie IL-2 versus IL-15-mediated proliferation of T cells. Proceedings of the National Academy of Sciences, 100, 14169-14174 https://doi.org/10.1073/pnas.2335979100
  10. Ehrhardt, A., Bartels, T., Klocke, R., Paul, D. and Halter, R. (2003): Increased susceptibility to the tobacco carcinogen 4-(methylnitrosamino )-1-(3-pyridyl)-1-butanone in transgenic mice overexpressing c-myc and epidermal growth factor in alveolar type II cells. J. Cancer Res. Clin. Oncol., 129, 71-75
  11. Fingar, D.C., Salama, S., Tsou, C., Harlow, E. and Blenis, J. (2002): Mammalian cell size in controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E. Genes and Development, 16, 1472-1487 https://doi.org/10.1101/gad.995802
  12. Gingras, A.C., Gygi, S.P., Raught, B. and Polakiewicz, R.D. (1999): Abraham R.T., Hoekstra M.F., Aebersold R., and Sonenberg N. Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism. Genes & Development, 1422- 1437
  13. Giraud, S., Greco, A., Brink, M., Diaz, J.J. and Delafontaine, P. (2001): Translation initiation of the insulin-like growth factor I receptor mRNA is mediated by an internal ribosome entry site. J. Biol. Chem., 23, 276, 5668-5675 https://doi.org/10.1074/jbc.M005928200
  14. Hecht, S.S., Morse, M.A., Amin, S., Stoner, G.D., Jordan, K.G., Choi, C.I. and Chung, F.L. (1989): Rapid single-dose model for lung tumor induction in A/J mice by 4-(methylnitrosamino )-1-(3-pyridyl)-1-butanone and the effect of diet. Carcinogenesis, (10), 1901-1904 https://doi.org/10.1093/carcin/10.10.1901
  15. Henis-Korenblit, S., Strumpf, N.L., Goldstaub, D. and Kimchi, A. (2000): A novel form of DAP5 protein accumulates in apoptotic cells as a result of caspase cleavage and internal ribosome entry site-mediated translation. Mol. Cell Biol., 20, 496-506 https://doi.org/10.1128/MCB.20.2.496-506.2000
  16. Hoffmann, D., Brunnemann, K.D., Prokopczyk, B. and Djordjevic, M.V. (1994): Tobacco-specific N-nitrosamines and Areca-derived N-nitrosamines: chemistry, biochemistry, carcinogenicity, and relevance to humans. J. Toxicol. Environ. Health, (1), 1-52 https://doi.org/10.1080/15287399409531825
  17. Holcik, M., Sonenberg, N. and Kormeluk, R.G. (2000): Internal ribosome initiation of translation and the control of cell death. Translation and Cell Death, 469-473 https://doi.org/10.1016/S0168-9525(00)02106-5
  18. Jaeschke, A., Dennis, P.B. and Thomas, G. (2004): mTOR: a mediator of intracellular homeostasis. Curr. Top. Microbiol. lmmunol., 279, 283-298
  19. Keyler, D., Pentel, P.R., Kuehl, G., Collins, G. and Murphy, S.E.: Effects of nicotine infusion on the metabolism of the tobacco carcinogen 4-(methylnitrosamino )-1-(3-pyridyl)-1butanone (NNK) in rats. Cancer Letter, 202, 1-9, 2003. Mitchell and Tollervey D. mRNA turnover. Curr. Opin. Cell Biol., 13, 320-325. 2001
  20. Perez, R., Wu, N., Klipfel, A.A. and Beart, R.W. Jr. (2003): A better cell cycle target for gene therapy of colorectal cancer: cyclin G. J. Gastrointest Surg., 7, 884-889 https://doi.org/10.1007/s11605-003-0034-8
  21. Pohjola, S.K., Lappi, M., Honkanen, M., Rantanen, L. and Savela, K. (2003): DNA binding of polycyclic aromatic hydrocarbons in a human bronchial epithelial cell line treated with diesel and gasoline particulate extracts and benzo[a]pyrene. Mutagenesis, 18, 429-438. https://doi.org/10.1093/mutage/geg021
  22. Smith, G.B., Bend, J.R., Bedard, L.L., Reid, K.R., Petsikas, D. and Massey, T.E. (2003): Biotransformation of 4-(methylnitrosamino )-1-(3-pyridyl)-1-butanone (NNK) in peripheral human lung microsomes. Drug Metab. Dispos., 31, 1134-1141 https://doi.org/10.1124/dmd.31.9.1134
  23. Yoneda, K., Chang, M.M., Chmiel, K., Chen, Y. and Wu, R. (2003): Application of high-density DNA microarray to study smoke- and hydrogen peroxide-induced injury and repair in human bronchial epithelial cells. J. Am. Soc. Nephrol., 14, S284-289 https://doi.org/10.1097/01.ASN.0000078023.30954.05
  24. Yu, C., Subler, M., Rahmani, M., Reese, E., Krystal, G., Conrad, D., Dent, P. and Grant, S. (2003): Induction of apoptosis in $BCR/ABL^{+}$ cells by histone deacetylase inhibitors involves reciprocal effects on the RAF/MEK/ERK and JNK pathways. Cancer Biol. Ther., 2, 544-551 https://doi.org/10.4161/cbt.2.5.454