This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Efeyan, A. Articles by Serrano, M. Search for Related Content PubMed PubMed Citation Articles by Efeyan, A. Articles by Serrano, M.

Induction of p53-Dependent Senescence by the MDM2 Antagonist Nutlin-3a in Mouse Cells of Fibroblast Origin

¹ Molecular Oncology Program, Spanish National Cancer Research Center (CNIO), Madrid, Spain and ² Discovery Oncology, Hoffmann-La Roche, Inc., Nutley, New Jersey

Requests for reprints: Manuel Serrano, Spanish National Cancer Research Center (CNIO), 3 Melchor Fernandez Almagro Street, Madrid E-28029, Spain. Phone: 34-91-732-8032; Fax: 34-91-732-8028; E-mail: mserrano{at}cnio.es.

Cellular senescence is emerging as an important in vivo anticancer response elicited by multiple stresses, including currently used chemotherapeutic drugs. Nutlin-3a is a recently discovered small-molecule antagonist of the p53-destabilizing protein murine double minute-2 (MDM2) that induces cell cycle arrest and apoptosis in cancer cells with functional p53. Here, we report that nutlin-3a induces cellular senescence in murine primary fibroblasts, oncogenically transformed fibroblasts, and fibrosarcoma cell lines. No evidence of drug-induced apoptosis was observed in any case. Nutlin-induced senescence was strictly dependent on the presence of functional p53 as revealed by the fact that cells lacking p53 were completely insensitive to the drug, whereas cells lacking the tumor suppressor alternative reading frame product of the CDKN2A locus underwent irreversible cell cycle arrest. Interestingly, irreversibility was achieved in neoplastic cells faster than in their corresponding parental primary cells, suggesting that nutlin-3a and oncogenic signaling cooperate in activating p53. Our current results suggest that senescence could be a major cellular outcome of cancer therapy by antagonists of the p53-MDM2 interaction, such as nutlin-3a. [Cancer Res 2007;67(15):7350–7]

This article has been cited by other articles:

				S. Shangary and S. Wang Targeting the MDM2-p53 Interaction for Cancer Therapy Clin. Cancer Res., September 1, 2008; 14(17): 5318 - 5324. [Abstract] [Full Text] [PDF]

				R. J. Jones, Q. Chen, P. M. Voorhees, K. H. Young, N. Bruey-Sedano, D. Yang, and R. Z. Orlowski Inhibition of the p53 E3 Ligase HDM-2 Induces Apoptosis and DNA Damage-Independent p53 Phosphorylation in Mantle Cell Lymphoma Clin. Cancer Res., September 1, 2008; 14(17): 5416 - 5425. [Abstract] [Full Text] [PDF]

				K. Kumamoto, E. A. Spillare, K. Fujita, I. Horikawa, T. Yamashita, E. Appella, M. Nagashima, S. Takenoshita, J. Yokota, and C. C. Harris Nutlin-3a Activates p53 to Both Down-regulate Inhibitor of Growth 2 and Up-regulate mir-34a, mir-34b, and mir-34c Expression, and Induce Senescence Cancer Res., May 1, 2008; 68(9): 3193 - 3203. [Abstract] [Full Text] [PDF]

				S. Shangary, D. Qin, D. McEachern, M. Liu, R. S. Miller, S. Qiu, Z. Nikolovska-Coleska, K. Ding, G. Wang, J. Chen, et al. Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition PNAS, March 11, 2008; 105(10): 3933 - 3938. [Abstract] [Full Text] [PDF]

				C. Saddler, P. Ouillette, L. Kujawski, S. Shangary, M. Talpaz, M. Kaminski, H. Erba, K. Shedden, S. Wang, and S. N. Malek Comprehensive biomarker and genomic analysis identifies p53 status as the major determinant of response to MDM2 inhibitors in chronic lymphocytic leukemia Blood, February 1, 2008; 111(3): 1584 - 1593. [Abstract] [Full Text] [PDF]