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Title: Activation of p53 by nutlin-3a induces apoptosis and cellular senescence in human glioblastoma multiforme
Author: Vilallonga Planells, Ruth
Coll Mulet, Llorenç
Martínez Soler, Fina
Castaño Boldú, Esther
Acebes Martín, Juan José
Giménez Bonafé, Pepita
Gil i Santano, Joan
Tortosa i Moreno, Avelina
Keywords: Glioma
Proteïnes supressores de tumors
Tumor suppressor protein
Issue Date: 5-Apr-2011
Publisher: Public Library of Science (PLoS)
Abstract: Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in adults. Despite concerted efforts to improve current therapies and develop novel clinical approaches, patient survival remains poor. As such, increasing attention has focused on developing new therapeutic strategies that specifically target the apoptotic pathway in order to improve treatment responses. Recently, nutlins, small-molecule antagonists of MDM2, have been developed to inhibit p53-MDM2 interaction and activate p53 signaling in cancer cells. Glioma cell lines and primary cultured glioblastoma cells were treated with nutlin-3a. Nutlin-3a induced p53-dependent G1- and G2-M cell cycle arrest and apoptosis in glioma cell lines with normal TP53 status. In addition, nutlin-arrested glioma cells show morphological features of senescence and persistent induction of p21 protein. Furthermore, senescence induced by nutlin-3a might be depending on mTOR pathway activity. In wild-type TP53 primary cultured cells, exposure to nutlin-3a resulted in variable degrees of apoptosis as well as cellular features of senescence. Nutlin-3a-induced apoptosis and senescence were firmly dependent on the presence of functional p53, as revealed by the fact that glioblastoma cells with knockdown p53 with specific siRNA, or cells with mutated or functionally impaired p53 pathway, were completely insensitive to the drug. Finally, we also found that nutlin-3a increased response of glioma cells to radiation therapy. The results provide a basis for the rational use of MDM2 antagonists as a novel treatment option for glioblastoma patients.
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It is part of: PLoS One, 2011, vol. 6, num. 4, p. 1-12
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ISSN: 1932-6203
Appears in Collections:Articles publicats en revistes (Infermeria Fonamental i Clínica)
Articles publicats en revistes (Ciències Fisiològiques)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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