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Anticancer Drugs. 2009 Sep;20(8):668-75. doi: 10.1097/CAD.0b013e32832d5159.

Involvement of N-acetyltransferase human in the cytotoxic activity of 5-fluorouracil.

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  • 1Division of Molecular and Genetic Medicine, Department of Genetic Medicine and Regenerative Therapeutics, Graduate School of Medicine, Tottori University, Nishimachi 36-1, Yonago 683-8504, Japan. kazuko@med.tottori-u.ac.jp


N-acetyltransferase human (NATH) participates in a posttranslational modification of the proteins and has been reported to play a role in apoptosis. In this study, the involvement of NATH in the cytotoxic action of 5-fluorouracil (5-FU) in human squamous cell carcinoma HEp-2 cells was examined. We found that 5-FU decreased NATH expression in a dose-dependent and time-dependent manner. No change was observed after treatment with bleomycin, nedaplatin, mitomycin C, or methotrexate. Interestingly, knockdown of NATH by small interfering RNA resulted in the downregulation of thymidylate synthase mRNA expression and induced apoptosis. Conversely, NATH overexpression facilitated cell proliferation independent of the presence of 5-FU. The effect of NATH knockdown on the expression of proteins in HEp-2 cells was examined using two-dimensional gel electrophoresis and mass spectrometry. Profilin 1, CutA, ras-related nuclear protein, annexin A5, enolase 1, and elongation factor 1 alpha 1 were found to be upregulated and 14-3-3eta, tublin, nuclear auto antigenic sperm protein, heat shock protein 70, and heat shock protein 90 were downregulated by knockdown of NATH. The results of this study suggest that NATH plays an important role in the cytotoxic activity of 5-FU.

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