title: P144, a Transforming Growth Factor beta inhibitor peptide, generates antitumoral effects and modifies SMAD7 and SKI levels in human glioblastoma cell lines.
abstract: Glioblastoma (GBM) is the most prevalent malignant primary brain tumor, accounting for 60-70% of all gliomas. Current median patient survival time is 14-16 months after diagnosis. Numerous efforts in therapy have not significantly altered the nearly uniform lethality of this malignancy. The Transforming Growth Factor beta (TGF-β) signaling pathway plays a key role in GBM and is implicated in proliferation, invasion and therapy resistance. Several inhibitors of the TGF-β pathway have entered clinical trials or are under development. In this work, the therapeutic potential of P144, a TGF-β inhibitor peptide, was analyzed. P144 decreased proliferation, migration, invasiveness, and tumorigenicity in vitro, whereas apoptosis and anoikis were significantly increased for GBM cell lines. SMAD2 phosphorylation was reduced, together with a downregulation of SKI and an upregulation of SMAD7 at both transcriptional and translational levels. Additionally, P144 was able to impair tumor growth and increase survival in an in vivo flank model. Our findings suggest a potential effect of P144 in vitro and in vivo that is mediated by regulation of transcriptional target genes of the TGF-β pathway, suggesting a therapeutic potential of P144 for GBM treatment.
authors.affiliation: Department of Biochemistry and Genetics, University of Navarra, Pamplona, Spain.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Gallo-Oller
authors.affiliation: Department of Neurology and Wilhelm Sander-NeuroOncology Unit, University Hospital Regensburg, Regensburg, Germany.
authors.forename: Arabel
authors.initials: A
authors.lastname: Vollmann-Zwerenz
authors.affiliation: Molecular Pathology Research Unit, Department of Pathology, Virgen de la Salud Hospital, Toledo, Spain.
authors.forename: Bárbara
authors.initials: B
authors.lastname: Meléndez
authors.affiliation: IdiPaz Research Unit, La Paz University Hospital, Madrid, Spain.
authors.forename: Juan A
authors.initials: JA
authors.lastname: Rey
authors.affiliation: Department of Neurology and Wilhelm Sander-NeuroOncology Unit, University Hospital Regensburg, Regensburg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Hau
authors.affiliation: Biohope SL, Tres Cantos, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Dotor
authors.affiliation: Department of Biochemistry and Genetics, University of Navarra, Pamplona, Spain. Electronic address: jscastresana@unav.es.
authors.forename: Javier S
authors.initials: JS
authors.lastname: Castresana
mesh_terms: D000818:Animals; D023102:Anoikis / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D010446:Peptide Fragments / Q000494:pharmacology*; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta; D015398:Signal Transduction / Q000187:drug effects; D051899:Smad2 Protein / Q000378:metabolism; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; C497806:SMAD7 protein, human; D051899:Smad2 Protein; D051906:Smad7 Protein; C504795:TGF-beta1 type III receptor (730-743), human; D016212:Transforming Growth Factor beta; C060614:SKI protein, human
keywords: Glioblastoma; P144; TGF-β inhibition; Transforming Growth Factor beta