title: BAG3 protein is overexpressed in human glioblastoma and is a potential target for therapy.
abstract: Glioblastoma multiforme, which represents 80% of malignant gliomas, is characterized by aggressiveness and high recurrence rates. Despite therapeutic advances, patients with glioblastoma multiforme show a poor survival, and identification of novel markers and molecular targets for therapy is needed. A role for BAG3, a member of the BAG family of HSC/HSP70 co-chaperones, in promoting tumor cell growth in vivo has recently been described. We analyzed BAG3 levels by IHC in specimens from patients affected by brain tumors and we found that BAG3, although negative in normal brain tissues, was highly expressed in astrocytic tumors and increasingly expressed in more aggressive types of cancer; it was particularly high in glioblastomas. Down-regulating BAG3 both in vitro and in vivo in a rat glioblastoma model resulted in increased sensitivity to apoptosis, suggesting that BAG3 is a potential target for novel therapies. Finally, we determined that the underlying molecular mechanism requires the formation of a complex of BAG3, HSP70, and BAX that prevents BAX translocation to mitochondria, thus protecting tumor cells from apoptosis. Our data identify BAG3 as a potential marker of glial brain tumor sensitivity to therapy and thus also an attractive candidate for new molecular therapies.
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences (FARMABIOMED), University of Salerno, Fisciano, Salerno, Italy.
authors.forename: Michelina
authors.initials: M
authors.lastname: Festa
authors.forename: Luis
authors.initials: L
authors.lastname: Del Valle
authors.forename: Kamel
authors.initials: K
authors.lastname: Khalili
authors.forename: Renato
authors.initials: R
authors.lastname: Franco
authors.forename: Giosuè
authors.initials: G
authors.lastname: Scognamiglio
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Graziano
authors.forename: Vincenzo
authors.initials: V
authors.lastname: De Laurenzi
authors.forename: Maria Caterina
authors.initials: MC
authors.lastname: Turco
authors.forename: Alessandra
authors.initials: A
authors.lastname: Rosati
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000328:Adult; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D003710:Demography; D005260:Female; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D058990:Molecular Targeted Therapy; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C414431:BAG3 protein, human; C498807:BAG3 protein, rat; D034741:RNA, Small Interfering; D051028:bcl-2-Associated X Protein