The Antiapoptotic Protein BAG3 Is Expressed in Thyroid Carcinomas and Modulates Apoptosis Mediated by Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand

Chiappetta, Gennaro; Ammirante, Massimo; Basile, Anna; Rosati, Alessandra; Festa, Michelina; Monaco, Mario; Vuttariello, Emilia; Pasquinelli, Rosa; Arra, Claudio; Zerilli, M; Todaro, Matilde; Stassi, Giorgio; Pezzullo, Luciano; Gentilella, Antonio; Tosco, Alessandra; Pascale, Maria; Marzullo, Liberato; Belisario, Maria Antonietta; Turco, Maria Caterina; Leone, Arturo

doi:10.1210/jc.2006-1712

Cited by 94 publications

(85 citation statements)

References 29 publications

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“…Constitutive BAG3 expression has been detected in several types of human cancers, such as glioblastoma, pancreatic carcinoma, leukemia and thyroid carcinoma, compared with very low basal levels of BAG3 in non-malignant cells. [25][26][27][28] Previously, BAG3 has been reported to support cancer cell survival by counteracting apoptosis. For example, BAG3 was shown to cooperate with the chaperone HSP70 to retain Bcl-2-associated X protein, BAX protein in the cytosol, which in turn prevented BAG3 mitigates proteotoxicity via selective autophagy F Rapino et al…”

Section: Discussionmentioning

confidence: 99%

BAG3 induction is required to mitigate proteotoxicity via selective autophagy following inhibition of constitutive protein degradation pathways

2013

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Simultaneous inhibition of the two major constitutive protein quality control (PQC) pathways, that is, the ubiquitin-proteasome system (UPS) and the aggresome-autophagy system, has been suggested as a promising strategy to trigger cell death in cancer cells. However, we observed that one third of rhabdomyosarcoma (RMS) cells survives parallel inhibition of the UPS by Bortezomib and the aggresome-autophagy pathway by the cytoplasmic histone deacetylase 6 inhibitor ST80, and is able to regrow upon drug removal, thus pointing to the induction of compensatory pathways. Here, we identify Bcl-2-associated athanogene 3 (BAG3) as a critical mediator of inducible resistance in surviving cells after concomitant blockage of constitutive PQC pathways by mitigating ST80/Bortezomib-triggered proteotoxicity via selective autophagy. ST80/Bortezomib cotreatment upregulates BAG3 mRNA and protein levels in surviving cells in addition to triggering the accumulation of insoluble protein aggregates. Intriguingly, knockdown of BAG3 by RNA interference severely impairs clearance of protein aggregates, significantly increases cell death and reduces longterm survival and clonogenic growth during recovery after ST80/Bortezomib cotreatment. Similarly, inhibition of autophagy by inducible autophagy-related protein 7 knockdown prevents removal of protein aggregates and cell regrowth during recovery after ST80/Bortezomib cotreatment. Also, the inhibition of lysosomal degradation using the V-ATPase pump inhibitor Bafilomycin A1 enhances accumulation of protein aggregates, and completely abolishes regrowth after Bortezomib/ST80-induced proteotoxic stress. By identifying BAG3 as a key mediator of inducible resistance by mitigating proteotoxicity via selective autophagy after inhibition of constitutive PQC systems, our study provides new insights into the regulation of PQC pathways in cancer cells and identifies new targets for therapeutic intervention.

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Section: Discussionmentioning

confidence: 99%

BAG3 induction is required to mitigate proteotoxicity via selective autophagy following inhibition of constitutive protein degradation pathways

2013

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“…Tumors excised after 2-week treatments were sectioned at a thickness of 6 μm. Immunohistochemistry was performed as described (20). Labeling of apoptotic cells was performed using the TUNEL ApopTag Peroxidase In Situ Apoptosis Detection kit (Intergen) following the manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

“…In humans, bag3 is constitutively expressed in myocytes and a few other normal cell types and in several tumors (leukemia and lymphoma, myeloma, and pancreas and thyroid carcinomas) (11,(16)(17)(18)(19)(20). In addition, its expression is induced in different normal cell types (leukocytes and epithelial and glial cells) in response to cell stressors, such as oxidants, high temperature, heavy metals, and HIV-1 infection (15,(21)(22)(23).…”

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

Ammirante

Rosati

Arra³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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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 bag3siRNA-adenovirus that down-regulates bag3 results in reduced tumor growth and increased animal survival.BAG3 | IKK-gamma | apoptosis

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“…From the first evidence of BAG3-mediated survival in B-CLLs, 5 a number of reports confirmed the anti-apoptotic activity of the protein in tumours of different compartments. 2,5 --20 Indeed, BAG3 down-modulation enhances apoptosis in leukaemia, 9 melanoma, 19 osteosarcoma, 19 glioblastoma 18,20 and thyroid carcinoma cells, 14 whereas its overexpression protects the cells from pro-apoptotic inputs (serum deprivation, oxidants and drugs). 19 Two principal elements contribute to the role of BAG3 in a vast range of tumours: bag3 induction by heat shock factor 1, 3 a transcription factor activated in many cancer types 21 and BAG3 ability to sustain NF-kB activity.…”

Section: Introductionmentioning

confidence: 99%

BAG3 controls angiogenesis through regulation of ERK phosphorylation

et al. 2012

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BAG3 is a co-chaperone of the heat shock protein (Hsp) 70, is expressed in many cell types upon cell stress, however, its expression is constitutive in many tumours. We and others have previously shown that in neoplastic cells BAG3 exerts an antiapoptotic function thus favoring tumour progression. As a consequence we have proposed BAG3 as a target of antineoplastic therapies. Here we identify a novel role for BAG3 in regulation of neo-angiogenesis and show that its downregulation results in reduced angiogenesis therefore expanding the role of BAG3 as a therapeutical target. In brief we show that BAG3 is expressed in endothelial cells and is essential for the interaction between ERK and its phosphatase DUSP6, as a consequence its removal results in reduced binding of DUSP6 to ERK and sustained ERK phosphorylation that in turn determines increased levels of p21 and p15 and cell-cycle arrest in the G1 phase.

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The Antiapoptotic Protein BAG3 Is Expressed in Thyroid Carcinomas and Modulates Apoptosis Mediated by Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand

Abstract: BAG3 downmodulates the apoptotic response to TRAIL in human neoplastic thyroid cells. The protein is specifically expressed in thyroid carcinomas and not in normal thyroid tissue or goiter.

Cited by 94 publications

References 29 publications

BAG3 induction is required to mitigate proteotoxicity via selective autophagy following inhibition of constitutive protein degradation pathways

BAG3 induction is required to mitigate proteotoxicity via selective autophagy following inhibition of constitutive protein degradation pathways

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

BAG3 controls angiogenesis through regulation of ERK phosphorylation

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