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


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Title: Activation of p53 by Nutlin-3a, an antagonist of MDM2, induces apoptosis and cellular senescence in adult T-cell leukemia cells.
Authors: Hasegawa, Hiroo / Yamada, Yasuaki / Iha, Hidekatsu / Tsukasaki, Kunihiro / Nagai, Kazuhiro / Atogami, Sunao / Sugahara, Kazuyuki / Tsuruda, Kazuto / Ishizaki, Akiko / Kamihira, Shimeru
Issue Date: Nov-2009
Publisher: Nature Publishing Group
Citation: Leukemia, 23(11), pp.2090–2101; 2009
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 p16(INK4a) and/or p14(ARF). 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-beta-galactosidase (SA-beta-gal) staining revealed that only ATL-related cell lines with wild-type p53 showed cellular senescence, although they lack both p16(INK4a) and p14(ARF). These results indicate that cellular senescence is an important event in p53-dependent cell death in ATL cells and is inducible without p16(INK4a) and p14(ARF). 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.Leukemia advance online publication, 27 August 2009; doi:10.1038/leu.2009.171.
Keywords: p53 / senescence / apoptosis / p14ARF / adult T-cell leukemia / Nutlin
URI: http://hdl.handle.net/10069/23199
ISSN: 08876924
DOI: 10.1038/leu.2009.171
PubMed ID: 19710698
Rights: © 2009 Nature Publishing Group
Type: Journal Article
Text Version: author
Appears in Collections:Articles in academic journal

Citable URI : http://hdl.handle.net/10069/23199

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