Molecular & Cellular Toxicology

The Korean Society of Toxicogenomics and Toxicoproteomics (대한독성유전 단백체학회)
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Toxicogenomics Study on TK6 Human Lymphoblast Cells Treated with Mitomycin C

  • Kim, Joo-Hwan (Department of Toxicological Researches, National Institute of Toxicological Research, Korea Food and Drug Administration) ;
  • Koo, Ye-Mo (Department of Toxicological Researches, National Institute of Toxicological Research, Korea Food and Drug Administration) ;
  • Lee, Woo-Sun (Department of Toxicological Researches, National Institute of Toxicological Research, Korea Food and Drug Administration) ;
  • Suh, Soo-Kyung (Department of Toxicological Researches, National Institute of Toxicological Research, Korea Food and Drug Administration) ;
  • Kang, Jin-Seok (Department of Toxicological Researches, National Institute of Toxicological Research, Korea Food and Drug Administration) ;
  • Han, Eui-Sik (Department of Toxicological Researches, National Institute of Toxicological Research, Korea Food and Drug Administration) ;
  • Kim, Seung-Hee (Department of Toxicological Researches, National Institute of Toxicological Research, Korea Food and Drug Administration) ;
  • Park, Sue-N. (Department of Toxicological Researches, National Institute of Toxicological Research, Korea Food and Drug Administration)
  • Published : 2007.09.30
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Abstract

Mitomycin C (MMC), an antitumor antibiotic isolated from Streptomyces caespitosus, is used in chemotherapy of gastric, bladder and colorectal cancer. MMC is activated in vivo to alkylate and crosslink DNA, via G-G interstrand bonds, thereby inhibiting DNA synthesis and transcription. This study investigates gene expression changes in response to MMC treatment in order to elucidate the mechanisms of MMC-induced toxicity. MMC was admistered with single dose (0.32 and 1.6 ${\mu}M$) to TK6 cells. Applied Biosystem's DNA chips were used for identifying the gene expression profile by MMC-induced toxicity. We identified up- or down-regulated 90 genes including cyclin M2, cyclin-dependent kinase inhibitor 1A (p21, cip1), programmed cell death 1, tumor necrosis factor (ligand) superfamily, member 9, et al. The regulated genes by MMC associated with the biological pathways apoptosis signaling pathway. Further characterization of these candidate markers related to the toxicity will be useful to understand the detailed mechanism of action of MMC.

Keywords

References

  1. Tennant, R. A. The National Center for toxicogenomics: using new technologies to inform mechanistic toxicology. Environ Health Perspect 107:A256-A258 (2002) https://doi.org/10.2307/3434534
  2. Aardema, M. J. & MacGregor, J. T. Toxicology and genetic toxicology in the new era of 'toxicogenomics'; impact of '-omics' technologies. Mutat Res 499:13-25 (2002) https://doi.org/10.1016/S0027-5107(01)00292-5
  3. Newton, R. K., Aaraderma, M. & Aubrecht, J. The utility of DNA microarrays for characterizing genotoxicity. Environ Health Perspect 112:420-422 (2004) https://doi.org/10.1289/ehp.6709
  4. Cheung, R. Y., Rauth, A. M. & Wu Yu. In vivo efficacy and toxicity of intratumorally delivered mitomycin C and its combination with doxorubicin using microsphere formulations. Anticancer Drugs 16:423-433 (2005) https://doi.org/10.1097/00001813-200504000-00009
  5. Joseph, P., Xu, Y. & Jaiswal, A. K. Non-enzymatic and enzymatic activation of mitomycin C: identification of a unique cytosolic activitiy. Int J Cancer 65: 263-271 (1996) https://doi.org/10.1002/(SICI)1097-0215(19960117)65:2<263::AID-IJC22>3.0.CO;2-D
  6. Hess, R. et al. Nuclear accumulation of p53 in response to treatment with DNA-damaging agents. Toxicol Lett 72:43-52 (1994) https://doi.org/10.1016/0378-4274(94)90008-6
  7. Palom, Y. et al. Structure of adduct X, the last unknown of the six major DNA adducts of mitomycin C formed in EMT6 mouse mammary tumor cells. Chem Res Toxicol 13:479-488 (2000) https://doi.org/10.1021/tx000024j
  8. Kastan, M. B. et al. Participationg of p53 protein in the cellular response to DNA damage. Cancer Res 51:6304-6311 (1991)
  9. Wilhelm, D., Bender, K., Knebel, A. & Angel, P. The level of intracellular glutathione is a key regulator for the induction of stress-activated signal transduction pathways including Jun N-terminal protein kinases and p38 kinase by alkylating agents. Mol Cell Biol 17:4792-4800 (1997) https://doi.org/10.1128/MCB.17.8.4792
  10. Zhu, K. Q. & Zhang, S. J. Involvement of ATM/ATR-p38 MAPK cascade in MNNG induced G1-S arrest. World J Gastroenterol 9:2073-2077 (2003) https://doi.org/10.3748/wjg.v9.i9.2073
  11. van Delft, J. M. H. et al. Discrimination of genotoxic from non-genotoxic carcinogen by gene expression profiling. Carcinogenesis 25:1265-1276 (2004) https://doi.org/10.1093/carcin/bgh108
  12. Levine, A. J. p53, the cellular gatekeeper for growth and division. Cell 88:323-331 (1997) https://doi.org/10.1016/S0092-8674(00)81871-1