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ABSTRACT: 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.
Biochimica et Biophysica Acta 06/2012; 1826(12):365-9. · 4.66 Impact Factor
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ABSTRACT: 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.
American Journal Of Pathology 06/2011; 178(6):2504-12. · 4.89 Impact Factor
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Anna Basile,
Rosario Zeppa,
Nicola Pasquino,
Claudio Arra,
Massimo Ammirante, Michelina Festa,
Antonio Barbieri,
Aldo Giudice,
Maria Pascale,
Maria Caterina Turco,
Alessandra Rosati
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ABSTRACT: 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.
Journal of Cellular Physiology 02/2011; 226(11):2901-7. · 3.87 Impact Factor
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Anna Basile,
Annarita Del Gatto,
Donatella Diana,
Rossella Di Stasi,
Antonia Falco, Michelina Festa,
Alessandra Rosati,
Antonio Barbieri,
Renato Franco,
Claudio Arra,
Carlo Pedone,
Roberto Fattorusso,
Maria Caterina Turco,
Luca Domenico D'Andrea
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ABSTRACT: 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.
Journal of Medicinal Chemistry 01/2011; 54(5):1391-400. · 4.80 Impact Factor
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ABSTRACT: Neoplasia pathogenesis and resistance to therapy are largely determined by acquired resistance to apoptosis. Among apoptosis-
regulating molecules, a role is emerging for BAG3, a member of the BAG co-chaperone protein family. Through its bag, WW and
prolix-rich domains, BAG3 protein can interact with a variety of molecular partners, including Hsc70/Hsp70, phospholipase
C- gamma and others. It has been recently shown that, in human primary lymphoid and myeloblastic leukemias, thyroid carcinoma
and other human tumours, BAG3 expression sustainscell survival and impairs cell response to therapy. Here we summarize findings
that assign to BAG3 an anti-apoptotic role in some neoplastic cell types, in addition to other biological activities, and
identify the protein as a candidate target of therapy.
KeywordsApoptosis-BAG3-cell survival-co-chaperone-tumour biology
01/2009: pages 137-146;
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Maria Fiammetta Romano, Michelina Festa,
Antonello Petrella,
Alessasndra Rosati,
Maria Pascale,
Rita Bisogni,
Vincenzo Poggi,
Elise C Kohn,
Salvatore Venuta,
Maria Caterina Turco,
Arturo Leone
Cancer biology & therapy 2(5):508-10. · 2.64 Impact Factor
