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1.
Semin Cell Dev Biol ; 78: 85-92, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-28864347

RESUMO

BAG3 is a multifunctional protein that can bind to heat shock proteins (Hsp) 70 through its BAG domain and to other partners through its WW domain, proline-rich (PXXP) repeat and IPV (Ile-Pro-Val) motifs. Its intracellular expression can be induced by stressful stimuli, while is constitutive in skeletal muscle, cardiac myocytes and several tumour types. BAG3 can modulate the levels, localisation or activity of its partner proteins, thereby regulating major cell pathways and functions, including apoptosis, autophagy, mechanotransduction, cytoskeleton organisation, motility. A secreted form of BAG3 has been identified in studies on pancreatic ductal adenocarcinoma (PDAC). Secreted BAG3 can bind to a specific receptor, IFITM2, expressed on macrophages, and induce the release of factors that sustain tumour growth and the metastatic process. BAG3 neutralisation therefore appears to constitute a novel potential strategy in the therapy of PDAC and, possibly, other tumours.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Carcinoma Ductal Pancreático/patologia , Proteínas de Choque Térmico HSP70/metabolismo , Neoplasias Pancreáticas/patologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Apoptose/fisiologia , Proteínas Reguladoras de Apoptose/genética , Autofagia/fisiologia , Biomarcadores Tumorais/sangue , Carcinoma Ductal Pancreático/genética , Humanos , Macrófagos/metabolismo , Mecanotransdução Celular/fisiologia , Proteínas de Membrana/metabolismo , Neoplasias Pancreáticas/genética , Comunicação Parácrina/fisiologia , Domínios Proteicos/fisiologia
2.
J Cell Physiol ; 232(2): 309-311, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27414463

RESUMO

Endometrioid endometrial cancer is the most common gynaecological tumor in developed countries, and its incidence is increasing. The definition of subtypes, based on clinical and endocrine features or on histopathological characteristics, correlate to some extent with patient's prognosis, but there is substantial heterogeneity within tumor types. The search for molecules and mechanisms implied in determining the progression and the response to therapy for this cancer is still ongoing. BAG3 protein, a member of BAG family of co-chaperones, has a pro-survival role in several tumor types. BAG3 anti-apoptotic properties rely on its characteristic to bind several intracellular partners, thereby, modulating crucial events such as apoptosis, differentiation, cell motility, and autophagy. BAG3 expression in human endometrial cancer tissues was not investigated so far. Here, we show that BAG3 protein levels are elevated in tumoral and hyperplastic cells in respect to normal glands. Furthermore, BAG3 subcellular localization appears to be changed in tumoral compared to normal cells. Our results indicate a possible role for BAG3 protein in the maintenance of cell survival in endometrioid endometrial cancer and suggest that this field of studies is worthy of further investigations. J. Cell. Physiol. 232: 309-311, 2017. © 2016 Wiley Periodicals, Inc.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Carcinoma Endometrioide/metabolismo , Neoplasias do Endométrio/metabolismo , Idoso , Idoso de 80 Anos ou mais , Carcinoma Endometrioide/patologia , Linhagem Celular Tumoral , Neoplasias do Endométrio/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Coloração e Rotulagem
4.
Biochim Biophys Acta ; 1826(2): 365-9, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22710027

RESUMO

The ability of BAG3, a member of the BAG family of heat shock protein (Hsp) 70 - cochaperones, to sustain the survival of human primary B-CLL and ALL cells was recognized about nine years ago. Since then, the anti-apoptotic activity of BAG3 has been confirmed in other tumor types, where it has been shown to regulate the intracellular concentration and localization of apoptosis-regulating factors, including NF-κB-activating (IKKγ) and Bcl2-family (Bax) proteins. Furthermore, growing evidences support its role in lymphoid and myeloid leukemia response to therapy. Moreover in the last years, the contribution of BAG3 to autophagy, a process known to be involved in the pathogenesis and response to therapy of leukemia cells, has been disclosed, opening a new avenue for the interpretation of the role of this protein in leukemias' biology.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Leucemia/terapia , Proteínas Adaptadoras de Transdução de Sinal/análise , Proteínas Reguladoras de Apoptose , Autofagia , Sobrevivência Celular , Humanos , Leucemia/patologia
5.
Am J Pathol ; 178(6): 2504-12, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21561597

RESUMO

Glioblastoma multiforme, which represents 80% of malignant gliomas, is characterized by aggressiveness and high recurrence rates. Despite therapeutic advances, patients with glioblastoma multiforme show a poor survival, and identification of novel markers and molecular targets for therapy is needed. A role for BAG3, a member of the BAG family of HSC/HSP70 co-chaperones, in promoting tumor cell growth in vivo has recently been described. We analyzed BAG3 levels by IHC in specimens from patients affected by brain tumors and we found that BAG3, although negative in normal brain tissues, was highly expressed in astrocytic tumors and increasingly expressed in more aggressive types of cancer; it was particularly high in glioblastomas. Down-regulating BAG3 both in vitro and in vivo in a rat glioblastoma model resulted in increased sensitivity to apoptosis, suggesting that BAG3 is a potential target for novel therapies. Finally, we determined that the underlying molecular mechanism requires the formation of a complex of BAG3, HSP70, and BAX that prevents BAX translocation to mitochondria, thus protecting tumor cells from apoptosis. Our data identify BAG3 as a potential marker of glial brain tumor sensitivity to therapy and thus also an attractive candidate for new molecular therapies.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Glioblastoma/metabolismo , Terapia de Alvo Molecular , Adulto , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular Tumoral , Demografia , Feminino , Técnicas de Silenciamento de Genes , Glioblastoma/patologia , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Transporte Proteico , RNA Interferente Pequeno/metabolismo , Ratos , Proteína X Associada a bcl-2/metabolismo
6.
J Cell Physiol ; 226(11): 2901-7, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21302292

RESUMO

The expression of the anti-apoptotic protein BAG3 is induced in several cell types by exposure to high temperature, oxidants, and other stressful agents. We investigated whether exposure to 50 Hz electromagnetic fields raised BAG3 levels in the human melanoma cell line M14, in vitro and in orthotopic xenografts. Exposure of cultured cells or xenografts for 6 h or 4 weeks, respectively, produced a significant (P < 0.01) increase in BAG3 protein amounts. Interestingly, at the same times, we could not detect any significant variation in the levels of HSP70/72 protein or cell apoptosis. These results confirm the stressful effect of exposure to ELF in human cells, by identifying BAG3 protein as a marker of ELF-induced stress. Furthermore, they suggest that BAG3 induction by ELF may contribute to melanoma cell survival and/or resistance to therapy.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Campos Eletromagnéticos , Melanoma/metabolismo , Neoplasias Cutâneas/metabolismo , Animais , Apoptose , Linhagem Celular Tumoral , Sobrevivência Celular , Feminino , Proteínas de Choque Térmico HSP70/metabolismo , Proteínas de Choque Térmico HSP72/metabolismo , Humanos , Camundongos , Camundongos Nus , Estresse Fisiológico
7.
Mol Oncol ; 13(6): 1388-1399, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30973679

RESUMO

We have previously shown that secreted BAG3 is a potential target for the treatment of pancreatic ductal adenocarcinoma and that pancreatic tumor growth and metastatic dissemination can be reduced by treatment with an anti-BAG3 murine antibody. Here, we used complementarity-determining region (CDR) grafting to generate a humanized version of the anti-BAG3 antibody that may be further developed for possible clinical use. We show that the humanized anti-BAG3 antibody, named BAG3-H2L4, abrogates BAG3 binding to macrophages and subsequent release of IL-6. Furthermore, it specifically localizes into tumor tissues and significantly inhibits the growth of Mia PaCa-2 pancreatic cancer cell xenografts. We propose BAG3-H2L4 antibody as a potential clinical candidate for BAG3-targeted therapy in pancreatic cancer.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Animais , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Ensaio de Imunoadsorção Enzimática , Feminino , Xenoenxertos , Humanos , Camundongos , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas
9.
Nat Commun ; 6: 8695, 2015 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-26522614

RESUMO

The incidence and death rate of pancreatic ductal adenocarcinoma (PDAC) have increased in recent years, therefore the identification of novel targets for treatment is extremely important. Interactions between cancer and stromal cells are critically involved in tumour formation and development of metastasis. Here we report that PDAC cells secrete BAG3, which binds and activates macrophages, inducing their activation and the secretion of PDAC supporting factors. We also identify IFITM-2 as a BAG3 receptor and show that it signals through PI3K and the p38 MAPK pathways. Finally, we show that the use of an anti-BAG3 antibody results in reduced tumour growth and prevents metastasis formation in three different mouse models. In conclusion, we identify a paracrine loop involved in PDAC growth and metastatic spreading, and show that an anti-BAG3 antibody has therapeutic potential.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Proliferação de Células , Macrófagos/citologia , Neoplasias Pancreáticas/metabolismo , Células Estromais/citologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Proteínas Reguladoras de Apoptose/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/fisiopatologia , Feminino , Humanos , Macrófagos/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/fisiopatologia , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Células Estromais/metabolismo , Neoplasias Pancreáticas
10.
Oncotarget ; 5(16): 6846-53, 2014 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-25149536

RESUMO

BAG3, member the HSP70 co-chaperones family, has been shown to play a relevant role in the survival, growth and invasiveness of different tumor types. In this study, we investigate the expression of BAG3 in 66 specimens from different lung tumors and the role of this protein in small cell lung cancer (SCLC) tumor growth. Normal lung tissue did not express BAG3 while we detected the expression of BAG3 by immunohistochemistry in all the 13 squamous cell carcinomas, 13 adenocarcinomas and 4 large cell carcinomas. Furthermore, we detected BAG3 expression in 22 of the 36 SCLCs analyzed. The role on SCLC cell survival was determined by down-regulating BAG3 levels in two human SCLC cell lines, i.e. H69 and H446, in vitro and measuring cisplatin induced apoptosis. Indeed down-regulation of BAG3 determines increased cell death and sensitizes cells to cisplatin treatment. The effect of BAG3 down-regulation on tumor growth was also investigated in an in vivo xenograft model by treating mice with an adenovirus expressing a specific bag3 siRNA. Treatment with bag3 siRNA-Ad significantly reduced tumor growth and improved animal survival. In conclusion we show that a subset of SCLCs over express BAG3 that exerts an anti-apoptotic effect resulting in resistance to chemotherapy.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Proteínas Reguladoras de Apoptose/biossíntese , Neoplasias Pulmonares/metabolismo , Carcinoma de Pequenas Células do Pulmão/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Antineoplásicos/farmacologia , Apoptose/fisiologia , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Processos de Crescimento Celular/fisiologia , Linhagem Celular Tumoral , Cisplatino/farmacologia , Regulação para Baixo , Feminino , Xenoenxertos , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/patologia
11.
J Med Chem ; 54(5): 1391-400, 2011 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-21280635

RESUMO

Angiogenesis is a fundamental process underlining physiological and pathological conditions. It is mainly regulated by the vascular endothelial growth factor (VEGF) and its receptors, which are the main targets of molecules able to modulate the angiogenic response. Pharmaceutical therapies based on antiangiogenic drugs represent a promising approach for the treatment of several socially important diseases. We report the biological and structural characterization of a VEGF receptor binder peptide designed on the N-terminal helix of VEGF. The reported experimental evidence shows that the peptide assumes in water a well-defined helical conformation and indicates that this peptide is a VEGF receptor antagonist and possesses antiangiogenic biological activity. In particular, it inhibits VEGF stimulated endothelial cell proliferation, activation, and survival, as well as angiogenesis and tumor progression in vivo. This peptide is a candidate for the development of novel peptide-based drugs for the treatment of diseases associated with excessive VEGF-dependent angiogenesis.


Assuntos
Inibidores da Angiogênese/síntese química , Peptídeos/síntese química , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Dicroísmo Circular , Células Endoteliais/metabolismo , Humanos , Espectroscopia de Ressonância Magnética , Melanoma Experimental/irrigação sanguínea , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/patologia , Camundongos , Camundongos Nus , Modelos Moleculares , Transplante de Neoplasias , Neovascularização Patológica , Peptídeos/química , Peptídeos/farmacologia , Estrutura Secundária de Proteína , Receptores de Fatores de Crescimento do Endotélio Vascular/química , Receptores de Fatores de Crescimento do Endotélio Vascular/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transplante Heterólogo , Veias Umbilicais/citologia , Água
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