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Oncogenes, Fusion Genes and Tumor Suppressor Genes

Activation of p53 by Nutlin-3a, an antagonist of MDM2, induces apoptosis and cellular senescence in adult T-cell leukemia cells

Leukemia volume 23, pages 2090–2101 (2009)Cite this article

Abstract

It has been reported that the induction of cellular senescence through p53 activation is an effective strategy in tumor regression. Unfortunately, however, tumors including adult T-cell leukemia/lymphoma (ATL) have disadvantages such as p53 mutations and a lack of p16INK4a and/or p14ARF. In this study we characterized Nutlin-3a-induced cell death in 16 leukemia/lymphoma cell lines. Eight cell lines, including six ATL-related cell lines, had wild-type p53 and Nutlin-3a-activated p53, and the cell lines underwent apoptosis or cell-cycle arrest, whereas eight cell lines with mutated p53 were resistant. Interestingly, senescence-associated-β-galactosidase (SA-β-gal) staining revealed that only ATL-related cell lines with wild-type p53 showed cellular senescence, although they lack both p16INK4a and p14ARF. These results indicate that cellular senescence is an important event in p53-dependent cell death in ATL cells and is inducible without p16INK4a and p14ARF. Furthermore, knockdown of Tp53-induced glycolysis and apoptosis regulator (TIGAR), a novel target gene of p53, by small interfering RNA(siRNA) indicated its important role in the induction of cellular senescence. As many patients with ATL carry wild-type p53, our study suggests that p53 activation by Nutlin-3a is a promising strategy in ATL. We also found synergism with a combination of Nutlin-3a and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), suggesting the application of Nutlin-3a-based therapy to be broader than expected.

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Acknowledgements

We are grateful to Dr Norman E. Sharpless, Departments of Medicine and Genetics, The Lineberger Comprehensive Cancer Center, The University of North Carolina, for his critical review and constructive suggestions on this article. This study was supported in part by a Grant-in-aid for Scientific Research (18590510) from the Japan Society for the Promotion of Science.

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Authors and Affiliations

  1. Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

    H Hasegawa, Y Yamada, S Atogami, K Sugahara, K Tsuruda, A Ishizaki & S Kamihira

  2. Department of Infectious Diseases, Faculty of Medicine, Oita University, Yufu, Oita, Japan

    H Iha

  3. Department of Hematology, Atomic Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

    K Tsukasaki

  4. Transfusion Service, Nagasaki University Hospital of Medicine and Dentistry, Nagasaki, Japan

    K Nagai

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  1. H Hasegawa
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Hasegawa, H., Yamada, Y., Iha, H. et al. Activation of p53 by Nutlin-3a, an antagonist of MDM2, induces apoptosis and cellular senescence in adult T-cell leukemia cells. Leukemia 23, 2090–2101 (2009). https://doi.org/10.1038/leu.2009.171

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