title: Disruption of prion protein-HOP engagement impairs glioblastoma growth and cognitive decline and improves overall survival.
abstract: Glioblastomas (GBMs) are resistant to current therapy protocols and identification of molecules that target these tumors is crucial. Interaction of secreted heat-shock protein 70 (Hsp70)-Hsp90-organizing protein (HOP) with cellular prion protein (PrP(C)) triggers a large number of trophic effects in the nervous system. We found that both PrP(C) and HOP are highly expressed in human GBM samples relative to non-tumoral tissue or astrocytoma grades I-III. High levels of PrP(C) and HOP were associated with greater GBM proliferation and lower patient survival. HOP-PrP(C) binding increased GBM proliferation in vitro via phosphatidylinositide 3-kinase and extracellular-signal-regulated kinase pathways, and a HOP peptide mimicking the PrP(C) binding site (HOP230-245) abrogates this effect. PrP(C) knockdown impaired tumor growth and increased survival of mice with tumors. In mice, intratumor delivery of HOP230-245 peptide impaired proliferation and promoted apoptosis of GBM cells. In addition, treatment with HOP230-245 peptide inhibited tumor growth, maintained cognitive performance and improved survival. Thus, together, the present results indicate that interfering with PrP(C)-HOP engagement is a promising approach for GBM therapy.
authors.affiliation: 1] International Research Center, AC Camargo Cancer Center, São Paulo, Brazil [2] Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil [3] National Institute for Translational Neuroscience and National Institute of Oncogenomics (CNPq/MCT/FAPESP), São Paulo, Brazil.
authors.forename: M H
authors.initials: MH
authors.lastname: Lopes
authors.affiliation: 1] International Research Center, AC Camargo Cancer Center, São Paulo, Brazil [2] National Institute for Translational Neuroscience and National Institute of Oncogenomics (CNPq/MCT/FAPESP), São Paulo, Brazil.
authors.forename: T G
authors.initials: TG
authors.lastname: Santos
authors.affiliation: 1] International Research Center, AC Camargo Cancer Center, São Paulo, Brazil [2] National Institute for Translational Neuroscience and National Institute of Oncogenomics (CNPq/MCT/FAPESP), São Paulo, Brazil.
authors.forename: B R
authors.initials: BR
authors.lastname: Rodrigues
authors.affiliation: 1] International Research Center, AC Camargo Cancer Center, São Paulo, Brazil [2] National Institute for Translational Neuroscience and National Institute of Oncogenomics (CNPq/MCT/FAPESP), São Paulo, Brazil.
authors.forename: N
authors.initials: N
authors.lastname: Queiroz-Hazarbassanov
authors.affiliation: Department of Pathology, AC Camargo Cancer Center, São Paulo, Brazil.
authors.forename: I W
authors.initials: IW
authors.lastname: Cunha
authors.affiliation: 1] International Research Center, AC Camargo Cancer Center, São Paulo, Brazil [2] National Institute for Translational Neuroscience and National Institute of Oncogenomics (CNPq/MCT/FAPESP), São Paulo, Brazil.
authors.forename: A P
authors.initials: AP
authors.lastname: Wasilewska-Sampaio
authors.affiliation: 1] International Research Center, AC Camargo Cancer Center, São Paulo, Brazil [2] National Institute for Translational Neuroscience and National Institute of Oncogenomics (CNPq/MCT/FAPESP), São Paulo, Brazil.
authors.forename: B
authors.initials: B
authors.lastname: Costa-Silva
authors.affiliation: 1] International Research Center, AC Camargo Cancer Center, São Paulo, Brazil [2] National Institute for Translational Neuroscience and National Institute of Oncogenomics (CNPq/MCT/FAPESP), São Paulo, Brazil [3] Inter-institutional Grad Program on Bioinformatics, Institute of Mathematics and Statistics, USP-São Paulo University, São Paulo, Brazil.
authors.forename: F A
authors.initials: FA
authors.lastname: Marchi
authors.affiliation: 1] Department of Pathology, Federal University of Paraná, Curitiba, Brazil [2] Pelé Pequeno Príncipe Research Institute, Curitiba, Brazil.
authors.forename: L F
authors.initials: LF
authors.lastname: Bleggi-Torres
authors.affiliation: Department of Neurosurgery, AC Camargo Cancer Center, São Paulo, Brazil.
authors.forename: P I
authors.initials: PI
authors.lastname: Sanematsu
authors.affiliation: Department of Neurosurgery, AC Camargo Cancer Center, São Paulo, Brazil.
authors.forename: S H
authors.initials: SH
authors.lastname: Suzuki
authors.affiliation: Department of Neurology, School of Medicine, University of São Paulo, Brazil.
authors.forename: S M
authors.initials: SM
authors.lastname: Oba-Shinjo
authors.affiliation: Department of Neurology, School of Medicine, University of São Paulo, Brazil.
authors.forename: S K N
authors.initials: SK
authors.lastname: Marie
authors.affiliation: Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, VIC, Australia.
authors.forename: E
authors.initials: E
authors.lastname: Toulmin
authors.affiliation: Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, VIC, Australia.
authors.forename: A F
authors.initials: AF
authors.lastname: Hill
authors.affiliation: 1] International Research Center, AC Camargo Cancer Center, São Paulo, Brazil [2] National Institute for Translational Neuroscience and National Institute of Oncogenomics (CNPq/MCT/FAPESP), São Paulo, Brazil [3] Ludwig Institute for Cancer Research, São Paulo, Brazil.
authors.forename: V R
authors.initials: VR
authors.lastname: Martins
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003071:Cognition; D003072:Cognition Disorders / Q000150:complications / Q000378:metabolism / Q000517:prevention & control*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000150:complications / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology*; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D060787:Neoplasm Grading; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011328:Prions / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D016019:Survival Analysis; D023041:Xenograft Model Antitumor Assays
chemical_list: D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D010446:Peptide Fragments; D011328:Prions