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  • Original Paper
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Anti-tumor activity of antizyme which targets the ornithine decarboxylase (ODC) required for cell growth and transformation

Oncogene volume 18, pages 165–172 (1999)Cite this article

Abstract

Cell proliferation and transformation induced by growth factor stimulation or by carcinogens, viruses, or oncogenes are characterized by an associated increase in polyamine levels, which is mediated by increased polyamine biosynthesis and enhanced uptake of polyamines. Polyamine biosynthesis is catalyzed particularly, in the level of ornithine decarboxylase (ODC). The elevation of cellular polyamine levels on the other hand accelerates the induction of ornithine decarboxylase antizyme (antizyme), which is involved not only in ODC-degradation, but in the negative regulation of polyamine transport. Taking advantage of these characteristics of antizyme, the potential of antizyme as a factor having anti-cell growth and anti-tumor activity was investigated. We show that antizyme can induce cell death associated with a rapid decline of intracellular polyamine contents. The possible anti-tumor activities of ectopically expressed antizyme were tested in p21H-ras (Val 12)-transformed NIH3T3 cells and several human malignant cell lines including a line with loss of p53 expression, and they were shown to be as sensitive as nontransformed NIH3T3 cells in vitro. The in vivo anti-tumor activity was also tested using nude mice inoculated with H-ras transformed NIH3T3 cells that had been transfected with inducible antizyme expression vector and the results showed that antizyme expression in vivo blocks tumor formation in these mice. These results suggest that ectopic antizyme expression is of possible therapeutic benefit in the treatment of cancer, which is mediated by ODC inactivation and intracellular polyamine depletion.

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Acknowledgements

This work was supported by a Grant-in-Aid for Pediatric Research from the Ministry of Health and Welfare, Japan, by a Grant-in-Aid for Cancer Research from the Ministry of Health and Welfare, Japan, by a Grant-in-Aid from the Ministry of Health and Welfare, Japan, by a comprehensive 10-year strategy for Cancer Control, by a Grant-in-Aid from the Ministry of Education, Science and Culture, Japan, by a Grant from the Human Science Foundation, Japan, and by a Grant from the Japan Leukemia Research Fund. We are grateful to Drs P Coffino (UCSF, USA) and Kadota (Idemitsu Central Reseach Center, Japan) for providing anti-ODC antibody. Mr Takemae, Hirabayashi, Mrs Komai and Kato are acknowledged for their help in cloning the cDNA of antizyme and for Western blotting analysis. We are grateful to Prof C Marshal (Institute for Cancer Research, London) for providing the p21H-ras (val 12) mutant clone. We would especially like to thank Dr S Matsufuji and Dr Y Murakami (Jikei University of Medical School, Japan) for antibody against anti-antizyme, measurement of ODC activity and encouragement in this work. S. Iwata is a National Institute post-doctoral fellow supported by Research Development Cooperation of Japan.

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Authors and Affiliations

  1. Department of Virology, The National Children's Medical Research Center, 3-35-31, Taishido, Setagaya-ku, 154, Tokyo, Japan

    Satoshi Iwata, Yuya Sato, Minoru Asada, Masatoshi Takagi, Atsumi Tsujimoto, Takayuki Yamada & Shuki Mizutani

  2. Department of Molecular Biology, Jichi Medical School, 3311-1, Yakushiji, Minami Kawachimachi, Tochigi, Japan

    Toshiya Inaba

  3. Department of Polymer Science and Engineering, Kyoto Institute of Technology, Goshokaido-cho, Matsugasaki, 606, Kyoto, Japan

    Shunji Sakamoto

  4. Department of Pediatrics, Tokyo Medical and Dental University, 1-5-45, Yushima, 113, Tokyo, Japan

    Jun-ichi Yata

  5. Faculty of Pharmaceutical Science, Chiba University, 1-33 Yayoi-cho, Chiba, Japan

    Tomomi Shimogori & Kazuei Igarashi

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  1. Satoshi Iwata
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Iwata, S., Sato, Y., Asada, M. et al. Anti-tumor activity of antizyme which targets the ornithine decarboxylase (ODC) required for cell growth and transformation. Oncogene 18, 165–172 (1999). https://doi.org/10.1038/sj.onc.1202275

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