title: Activation of p53 by nutlin-3a induces apoptosis and cellular senescence in human glioblastoma multiforme.
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.
authors.affiliation: Departament de Ciències Fisiològiques II, Institut d'Investigació Biomèdica de Bellvitge-Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Ruth
authors.initials: R
authors.lastname: Villalonga-Planells
authors.forename: Llorenç
authors.initials: L
authors.lastname: Coll-Mulet
authors.forename: Fina
authors.initials: F
authors.lastname: Martínez-Soler
authors.forename: Esther
authors.initials: E
authors.lastname: Castaño
authors.forename: Juan-Jose
authors.initials: JJ
authors.lastname: Acebes
authors.forename: Pepita
authors.initials: P
authors.lastname: Giménez-Bonafé
authors.forename: Joan
authors.initials: J
authors.lastname: Gil
authors.forename: Avelina
authors.initials: A
authors.lastname: Tortosa
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects* / Q000528:radiation effects; D020868:Gene Silencing; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D009154:Mutation; D010879:Piperazines / Q000494:pharmacology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D007093:Imidazoles; D010879:Piperazines; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; D051736:Proto-Oncogene Proteins c-mdm2