IKK{gamma} protein is a target of BAG3 regulatory activity in human tumor growth.
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.
Ammirante
Massimo
M
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.
Rosati
Alessandra
A
Arra
Claudio
C
Basile
Anna
A
Falco
Antonia
A
Festa
Michela
M
Pascale
Maria
M
d'Avenia
Morena
M
Marzullo
Liberato
L
Belisario
Maria Antonietta
MA
De Marco
Margot
M
Barbieri
Antonio
A
Giudice
Aldo
A
Chiappetta
Gennaro
G
Vuttariello
Emilia
E
Monaco
Mario
M
Bonelli
Patrizia
P
Salvatore
Gaetano
G
Di Benedetto
Maria
M
Deshmane
Satish L
SL
Khalili
Kamel
K
Turco
Maria Caterina
MC
Leone
Arturo
A
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
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