title: Gastrin-Releasing Peptide Receptor Knockdown Induces Senescence in Glioblastoma Cells.
abstract: Glioblastoma multiforme (GBM) is the most aggressive type of brain tumor, characterized by excessive cell proliferation, resistance to apoptosis, and invasiveness. Due to resistance to currently available treatment options, the prognosis for patients with GBM is very dismal. The activation of gastrin-releasing peptide receptors (GRPR) stimulates GBM cell proliferation, whereas GRPR antagonists induce antiproliferative effects in in vitro and in vivo experimental models of GBM. However, the role of GRPR in regulating other aspects of GBM cell function related to tumor progression remains poorly understood, and previous studies have not used RNA interference techniques as tools to examine GRPR function in GBM. Here, we found that stable GRPR knockdown by a lentiviral vector using a short hairpin interfering RNA sequence in human A172 GBM cells resulted in increased cell size and altered cell cycle dynamics consistent with cell senescence. These changes were accompanied by increases in the content of p53, p21, and p16, activation of epidermal growth factor receptors (EGFR), and a reduction in p38 content. These results increase our understanding of GRPR regulation of GBM cells and further support that GRPR may be a relevant therapeutic target in GBM.
authors.affiliation: Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, 90035-003, Porto Alegre, RS, Brazil.|Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Rua Sarmento Leite, 500 (ICBS, Campus Centro/UFRGS), 90050-170, Porto Alegre, RS, Brazil.
authors.forename: Pâmela Rossi
authors.initials: PR
authors.lastname: Menegotto
authors.affiliation: Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, 90035-003, Porto Alegre, RS, Brazil.|Graduate Program in Gastroenterology and Hepatology, School of Medicine, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Patrícia Luciana
authors.initials: PL
authors.lastname: da Costa Lopez
authors.affiliation: Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, 90035-003, Porto Alegre, RS, Brazil.|Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Rua Sarmento Leite, 500 (ICBS, Campus Centro/UFRGS), 90050-170, Porto Alegre, RS, Brazil.
authors.forename: Bárbara Kunzler
authors.initials: BK
authors.lastname: Souza
authors.affiliation: Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, 90035-003, Porto Alegre, RS, Brazil.|Children's Cancer Institute, 90420-140, Porto Alegre, RS, Brazil.
authors.forename: Caroline Brunetto
authors.initials: CB
authors.lastname: de Farias
authors.affiliation: Graduate Program in Gastroenterology and Hepatology, School of Medicine, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.|Department of Biophysics, Laboratory of Cellular Plasticity and Signaling, Institute of Biosciences, and Center of Biotechnology, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Eduardo Cremonese
authors.initials: EC
authors.lastname: Filippi-Chiela
authors.affiliation: Laboratory of Genomic Medicine, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, 90035-003, Porto Alegre, RS, Brazil.
authors.forename: Igor Araújo
authors.initials: IA
authors.lastname: Vieira
authors.affiliation: Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, 90035-003, Porto Alegre, RS, Brazil.|Department of Internal Medicine, Faculty of Medicine, Federal University of Rio Grande do Sul, 90035-003, Porto Alegre, RS, Brazil.
authors.forename: Gilberto
authors.initials: G
authors.lastname: Schwartsmann
authors.affiliation: Department of Biophysics, Laboratory of Cellular Plasticity and Signaling, Institute of Biosciences, and Center of Biotechnology, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Guido
authors.initials: G
authors.lastname: Lenz
authors.affiliation: Cancer and Neurobiology Laboratory, Experimental Research Center, Clinical Hospital (CPE-HCPA), Federal University of Rio Grande do Sul, 90035-003, Porto Alegre, RS, Brazil. rroesler@terra.com.br.|Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, Rua Sarmento Leite, 500 (ICBS, Campus Centro/UFRGS), 90050-170, Porto Alegre, RS, Brazil. rroesler@terra.com.br.
authors.forename: Rafael
authors.initials: R
authors.lastname: Roesler
mesh_terms: D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D016922:Cellular Senescence / Q000502:physiology*; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D018004:Receptors, Bombesin / Q000172:deficiency* / Q000235:genetics
chemical_list: D018004:Receptors, Bombesin
keywords: Bombesin receptor; Brain tumor; Cell senescence; Gastrin-releasing peptide receptor; Glioblastoma; RNA interference