title: IKK{gamma} protein is a target of BAG3 regulatory activity in human tumor growth.
abstract: BAG3, a member of the BAG family of heat shock protein (HSP) 70 cochaperones, is expressed in response to stressful stimuli in a number of normal cell types and constitutively in a variety of tumors, including pancreas carcinomas, lymphocytic and myeloblastic leukemias, and thyroid carcinomas. Down-regulation of BAG3 results in cell death, but the underlying molecular mechanisms are still elusive. Here, we investigated the molecular mechanism of BAG3-dependent survival in human osteosarcoma (SAOS-2) and melanoma (M14) cells. We show that bag3 overexpression in tumors promotes survival through the NF-kappaB pathway. Indeed, we demonstrate that BAG3 alters the interaction between HSP70 and IKKgamma, increasing availability of IKKgamma and protecting it from proteasome-dependent degradation; this, in turn, results in increased NF-kappaB activity and survival. These results identify bag3 as a potential target for anticancer therapies in those tumors in which this gene is constitutively expressed. As a proof of principle, we show that treatment of a mouse xenograft tumor model with bag3siRNA-adenovirus that down-regulates bag3 results in reduced tumor growth and increased animal survival.
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology and Cancer Center, School of Medicine, University of California, San Diego, La Jolla, CA 92093-0723, USA.
authors.forename: Massimo
authors.initials: M
authors.lastname: Ammirante
authors.forename: Alessandra
authors.initials: A
authors.lastname: Rosati
authors.forename: Claudio
authors.initials: C
authors.lastname: Arra
authors.forename: Anna
authors.initials: A
authors.lastname: Basile
authors.forename: Antonia
authors.initials: A
authors.lastname: Falco
authors.forename: Michela
authors.initials: M
authors.lastname: Festa
authors.forename: Maria
authors.initials: M
authors.lastname: Pascale
authors.forename: Morena
authors.initials: M
authors.lastname: d'Avenia
authors.forename: Liberato
authors.initials: L
authors.lastname: Marzullo
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Belisario
authors.forename: Margot
authors.initials: M
authors.lastname: De Marco
authors.forename: Antonio
authors.initials: A
authors.lastname: Barbieri
authors.forename: Aldo
authors.initials: A
authors.lastname: Giudice
authors.forename: Gennaro
authors.initials: G
authors.lastname: Chiappetta
authors.forename: Emilia
authors.initials: E
authors.lastname: Vuttariello
authors.forename: Mario
authors.initials: M
authors.lastname: Monaco
authors.forename: Patrizia
authors.initials: P
authors.lastname: Bonelli
authors.forename: Gaetano
authors.initials: G
authors.lastname: Salvatore
authors.forename: Maria
authors.initials: M
authors.lastname: Di Benedetto
authors.forename: Satish L
authors.initials: SL
authors.lastname: Deshmane
authors.forename: Kamel
authors.initials: K
authors.lastname: Khalili
authors.forename: Maria Caterina
authors.initials: MC
authors.lastname: Turco
authors.forename: Arturo
authors.initials: A
authors.lastname: Leone
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C414431:BAG3 protein, human; D018840:HSP70 Heat-Shock Proteins; D016328:NF-kappa B; D034741:RNA, Small Interfering; D051550:I-kappa B Kinase