The anti-apoptotic BAG3 protein is expressed in lung carcinomas and regulates small cell lung carcinoma (SCLC) tumor growth

Chiappetta, Gennaro; Basile, Anna; Barbieri, Antônio; Falco, Antonia; Rosati, Alessandra; Festa, Michelina; Pasquinelli, Rosa; Califano, Daniela; Palma, Giuseppe; Costanzo, Raffaele; Barcaroli, Daniela; Coccia, Mario; Franco, Renato; Rocco, Gaetano; Pascale, Maria; Turco, Maria Caterina; Laurenzi, Vincenzo De; Arra, Claudio

doi:10.18632/oncotarget.2261

Cited by 31 publications

(33 citation statements)

References 19 publications

(33 reference statements)

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“…The BAG3 gene is a transcriptional target of the stress-induced transcription factor HSF1 which was found to be upregulated in glioma (44). In addition to glioblastoma, overexpression of BAG3 has been observed in different types of tumors including pancreatic carcinoma, leukemia, small cell lung cancer, and thyroid carcinoma, compared with very low basal levels of BAG3 in non-malignant cells (20,21,(45)(46)(47). The role of BAG3 in promoting cell survival may therefore enhance therapy resistance in glioblastoma and several other human neoplasms.…”

Section: Discussionmentioning

confidence: 99%

Interference with the HSF1/HSP70/BAG3 Pathway Primes Glioma Cells to Matrix Detachment and BH3 Mimetic–Induced Apoptosis

Antonietti

Linder

Hehlgans

et al. 2017

Molecular Cancer Therapeutics

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Malignant gliomas exhibit a high intrinsic resistance against stimuli triggering apoptotic cell death. HSF1 acts as transcription factor upstream of HSP70 and the HSP70 co-chaperone BAG3 that is overexpressed in glioblastoma. To specifically target this resistance mechanism, we applied the selective HSF1 inhibitor KRIBB11 and the HSP70/BAG3 interaction inhibitor YM-1 in combination with the pan-Bcl-2 inhibitor AT-101. Here, we demonstrate that lentiviral BAG3 silencing significantly enhances AT-101-induced cell death and reactivates effector caspase-mediated apoptosis in U251 glioma cells with high BAG3 expression, whereas these sensitizing effects were less pronounced in U343 cells expressing lower BAG3 levels. KRIBB11 decreased protein levels of HSP70, BAG3, and the antiapoptotic Bcl-2 protein Mcl-1, and both KRIBB11 and YM-1 elicited significantly increased mitochondrial dysfunction, effector caspase activity, and apoptotic cell death after combined treatment with AT-101 and ABT-737. Depletion of BAG3 also led to a pronounced loss of cell-matrix adhesion, FAK phosphorylation, and in vivo tumor growth in an orthotopic mouse glioma model. Furthermore, it reduced the plating efficiency of U251 cells in three-dimensional clonogenic assays and limited clonogenic survival after short-term treatment with AT-101. Collectively, our data suggest that the HSF1/HSP70/BAG3 pathway plays a pivotal role for overexpression of prosurvival Bcl-2 proteins and cell death resistance of glioma. They also support the hypothesis that interference with BAG3 function is an effective novel approach to prime glioma cells to anoikis. Mol Cancer Ther; 16(1); 156-68. ©2016 AACR.

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Section: Discussionmentioning

confidence: 99%

Interference with the HSF1/HSP70/BAG3 Pathway Primes Glioma Cells to Matrix Detachment and BH3 Mimetic–Induced Apoptosis

Antonietti

Linder

Hehlgans

et al. 2017

Molecular Cancer Therapeutics

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“…In addition, BAG3 expression is increased in a large number of cancers including: acute lymphocytic and B cell chronic lymphocytic leukemia [52, 53] thyroid carcinoma [54]; melanomas [55] non-small-cell lung cancer [56]; hepatocellular carcinoma [57]; pancreatic adenocarcinoma [58], small cell carcinoma of the lung [59] and glioblastoma [60]. The overexpression of BAG3 in malignant cells increased motility and metastasis, whereas reduction in BAG3 protein by RNA interference decreased cell motility.…”

Section: Bag3 Mutants Myofibrillar Myopathy and Dilated Cardiomyopathymentioning

confidence: 99%

BAG3: a new player in the heart failure paradigm

et al. 2015

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BAG3 is a cellular protein that is expressed predominantly in skeletal and cardiac muscle but can also be found in the brain and in the peripheral nervous system. BAG3 functions in the cell include: serving as a co-chaperone with members of the heat-shock protein family of proteins to facilitate the removal of misfolded and degraded proteins, inhibiting apoptosis by interacting with Bcl2 and maintaining the structural integrity of the Z-disk in muscle by binding with CapZ. The importance of BAG3 in the homeostasis of myocytes and its role in the development of heart failure was evidenced by the finding that single allelic mutations in BAG3 were associated with familial dilated cardiomyopathy. Furthermore, significant decreases in the level of BAG3 have been found in end-stage failing human heart and in animal models of heart failure including mice with heart failure secondary to trans-aortic banding and in pigs after myocardial infarction. Thus, it becomes relevant to understand the cellular biology and molecular regulation of BAG3 expression in order to design new therapies for the treatment of patients with both hereditary and non-hereditary forms of dilated cardiomyopathy.

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“…In addition to the BAG domain, BAG3 contains a WW domain near its N-terminus and a proline-rich region (multiple PXXP motifs) (16,17), and our earlier study showed that BAG3 also regulates cell motility and tumor growth, invasion and metastasis (18). Moreover, several lines of evidence indicate that downregulation of BAG3 enhances chemotherapy-mediated apoptosis among cancer cells (19)(20)(21), which is consistent with the recent finding that BAG3 stabilizes Mcl-1, Bcl-2 and Bcl-X L , thereby promoting cancer cell survival (22,23). The precise mechanism by which BAG3 exerts these effects remains unclear.…”

Section: Introductionmentioning

confidence: 99%

BAG3-mediated Mcl-1 stabilization contributes to drug resistance via interaction with USP9X in ovarian cancer

Habata

Iwasaki

Sugio

et al. 2016

International Journal of Oncology

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Abstract. Paclitaxel in combination with carboplatin improves survival among patients with susceptible ovarian cancers, but no strategy has been established against resistant ovarian cancers. BAG3 (Bcl-2-associated athanogene 3) is one of six BAG family proteins, which are involved in such cellular processes as proliferation, migration and apoptosis. In addition, expression of BAG3 with Mcl-1, a Bcl-2 family protein, reportedly associates with resistance to chemotherapy. Our aim in this study was to evaluate the functional role of BAG3 and Mcl-1 in ovarian cancer chemoresistance and explore possible new targets for treatment. We found that combined expression of BAG3 and Mcl-1 was significantly associated with a poor prognosis in ovarian cancer patients. In vitro, BAG3 knockdown in ES2 clear ovarian cancer cells significantly increased the efficacy of paclitaxel in combination with the Mcl-1 antagonist MIM1, with or without the Bcl-2 family antagonist ABT737. Moreover, BAG3 was found to positively regulate Mcl-1 levels by binding to and inhibiting USP9X. Our data show that BAG3 and Mcl-1 are key mediators of resistance to chemotherapy in ovarian cancer. In BAG3 knockdown ES2 clear ovarian cancer cells, combination with ABT737 and MIM1 enhanced the efficacy of paclitaxel. These results suggest that inhibiting BAG3 in addition to antiapoptotic Bcl-2 family proteins may be a useful therapeutic strategy for the treatment of chemoresistant ovarian cancers.

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The anti-apoptotic BAG3 protein is expressed in lung carcinomas and regulates small cell lung carcinoma (SCLC) tumor growth

Cited by 31 publications

References 19 publications

Interference with the HSF1/HSP70/BAG3 Pathway Primes Glioma Cells to Matrix Detachment and BH3 Mimetic–Induced Apoptosis

Interference with the HSF1/HSP70/BAG3 Pathway Primes Glioma Cells to Matrix Detachment and BH3 Mimetic–Induced Apoptosis

BAG3: a new player in the heart failure paradigm

BAG3-mediated Mcl-1 stabilization contributes to drug resistance via interaction with USP9X in ovarian cancer

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