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IKKγ protein is a target of BAG3 regulatory activity in human tumor growth

2010; National Academy of Sciences; Volume: 107; Issue: 16 Linguagem: Inglês

10.1073/pnas.0907696107

1091-6490

Massimo Ammirante, Alessandra Rosati, Claudio Arra, Anna Basile, Antonia Falco, Michela Festa, Maria Pascale, Morena d’Avenia, Liberato Marzullo, Maria Antonietta Belisario, Margot De Marco, Antônio Barbieri, Aldo Giudice, Gennaro Chiappetta, Emilia Vuttariello, Mario Monaco, Patrizia Bonelli, Gaetano Salvatore, Maria Benedetto, Satish L. Deshmane, Kamel Khalili, Maria Caterina Turco, Arturo Leone,

Probabilistic and Robust Engineering Design

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-κB pathway. Indeed, we demonstrate that BAG3 alters the interaction between HSP70 and IKKγ, increasing availability of IKKγ and protecting it from proteasome-dependent degradation; this, in turn, results in increased NF-κB 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 bag3 siRNA-adenovirus that down-regulates bag3 results in reduced tumor growth and increased animal survival.