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Pancreatic ductal adenoma carcinoma (PDAC) is considered one of the deadliest solid cancers as it is usually diagnosed in advanced stages and has a poor response to treatment. The enormous effort made in the last 2 decades in the oncology field has not led to significant progress in improving early diagnosis or therapy for PDAC. The stroma of PDAC plays an active role in tumour initiation and progression and includes immune cells and stromal cells. We previously reported that Bcl2-associated athanogene (BAG3) secreted by PDAC cells activates tumour-associated macrophages to promote tumour growth. The disruption of this tumour-stroma axis by the anti-BAG3 H2L4 therapeutic antibody is sufficient to delay tumour growth and limit metastatic spreading in different PDAC preclinical models. In the present study, we examined the role of BAG3 to activate human fibroblasts (HF) in releasing cytokines capable of supporting tumour progression. Treatment of fibroblasts with recombinant BAG3 induced important changes in the organisation of the cytoskeleton of these cells and stimulated the production of interleukin-6, monocyte chemoattractant protein-1/C-C motif chemokine ligand 2, and hepatocyte growth factor. Specifically, we observed that BAG3 triggered a depolymerisation of microtubules at the periphery of the cell while they were conserved in the perinuclear area. Conversely, the vimentin-based intermediate filaments increased and spread to the edges of the cells. Finally, the conditioned medium (CM) collected from BAG3-treated HF promoted the survival, proliferation, and migration of the PDAC cells. Blocking of the PDAC-fibroblast axis by the H2L4 therapeutic anti-BAG3 antibody, resulted in inhibition of cytokine release and, consequently, the inhibition of the migratory phenotype conferred by the CM to PDAC cells., (© 2021 The Authors. Journal of Cellular Biochemistry published by Wiley Periodicals LLC.)

Hypoxia and angiogenesis in solid tumors are often strictly linked to the development of fibrotic tissues, a detrimental event that compromises the antitumor immunity. As a consequence, tumor aggressiveness and poor patient prognosis relate to higher incidence of tissue fibrosis and stromal stiffness. The molecular pathways through which normal fibroblasts are converted in cancer-associated fibroblasts (CAFs) have a central role in the onset of fibrosis in tumor stroma, thus emerging as a strategic target of novel therapeutic approaches for cancer disease. Several studies addressed the role of BAG3 in sustaining growth and survival of cancer cell and also shed light on the different mechanisms in which the intracellular protein is involved. More recently, new pieces of evidence revealed a pivotal role of extracellular BAG3 in pro-tumor cell signaling in the tumor microenvironment, as well as its involvement in the development of fibrosis in tumor tissues. Here we report further data showing the presence of the BAG3 receptor (Interferon-induced transmembrane protein [IFITM]-2) on the plasma membrane of normal dermal fibroblasts and the activity of BAG3 as a factor able to induce the expression of α-smooth muscle actin and the phosphorylation of AKT and focal adhesion kinase, that sustain CAF functions in tumor microenvironment. Furthermore, in agreement with these findings, bag3 gene expression has been analyzed by high throughput RNA sequencing databases from patients-derived xenografts. A strong correlation between bag3 gene expression and patients' survival was found in several types of fibrotic tumors. The results obtained provide encouraging data that identify BAG3 as a promising therapeutic target to counteract fibrosis in tumors., (© 2021 The Authors. Journal of Cellular Biochemistry Published by Wiley Periodicals LLC.)

BAG3 is a member of human BAG (Bcl-2-associated athanogene) proteins and plays a role in apoptosis, cell adhesion, cytoskeleton remodeling, and autophagy. The aim of this study was to evaluate BAG3 levels in healthy subjects, hypertensive patients, and hypertensive diabetic patients. We enrolled 209 Caucasian adults, of both sex, 18-75 years of age, 77 were healthy controls, 62 were affected by hypertension, and 70 were affected by hypertension and type 2 diabetes. All patients underwent an assessment that included medical history, physical examination, vital signs, a 12-lead electrocardiogram, measurements of systolic (SBP), and diastolic blood pressure (DBP), heart rate (HR), fasting plasma glucose (FPG), glycated hemoglobin (HbA 1c ), triglycerides (TG), transaminases, high sensitivity C-reactive protein (Hs-CRP), and BAG3. We observed higher blood pressure values in hypertensive, and hypertensive diabetic patients compared to controls. As expected, FPG and HbA 1c were higher in diabetic hypertensive patients, compared to the other two groups. No Tg levels differences were recorded among the three groups. Hs-CRP was higher in diabetic hypertensive patients compared to healthy subjects. Finally, BAG3 levels were higher in hypertensives, and hypertensive diabetic patients compared to controls. We observed higher levels of BAG3 in hypertensive patients compared to healthy controls, and even higher levels in hypertensive diabetic patients compared to healthy subjects. This paper could be the first of a long way to identify potential involvement of deregulated BAG3 levels in cardiometabolic diseases., (© 2017 Wiley Periodicals, Inc.)

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., (© 2016 Wiley Periodicals, Inc.)

Autophagy is an evolutionarily conserved, selective degradation pathway of cellular components that is important for cell homeostasis under healthy and pathologic conditions. Here we demonstrate that an increase in the level of BAG3 results in stimulation of autophagy in glioblastoma cells. BAG3 is a member of a co-chaperone family of proteins that associates with Hsp70 through a conserved BAG domain positioned near the C-terminus of the protein. Expression of BAG3 is induced by a variety of environmental changes that cause stress to cells. Our results show that BAG3 overexpression induces autophagy in glioma cells. Interestingly, inhibition of the proteasome caused an increase in BAG3 levels and induced autophagy. Further analysis using specific siRNA against BAG3 suggests that autophagic activation due to proteosomal inhibition is mediated by BAG3. Analyses of BAG3 domain mutants suggest that the WW domain of BAG3 is crucial for the induction of autophagy. BAG3 overexpression also increased the interaction between Bcl2 and Beclin-1, instead of disrupting them, suggesting that BAG3 induced autophagy is Beclin-1 independent. These observations reveal a novel role for the WW domain of BAG3 in the regulation of autophagy., (© 2014 Wiley Periodicals, Inc.)

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., (Copyright © 2011 Wiley-Liss, Inc.)

We previously identified apoptosis-induced regulator (air) as a pro-apoptotic transcript whose expression was repressed by NF-κB/Rel activity in the human leukemia cell line Jurkat (Turco, Lamberti, Bisogni, Romano, Petrella, Ammirante, Rosati, d'Avenia, Arra, Spugnini, Venuta, 2007, Leukemia 21:2557-2559). In this paper, we report that air sequence is detectable by Southern blot in human healthy donors (HHD) leukocytes and in two pancreatic adenocarcinoma cell lines (AsPC-1 and PANC-1), providing the first definitive evidence of air gene presence in human genome. In addition, we demonstrate that air expression is induced in the tumor cell lines by a naturally occurring ROS-inducing compound, phenethyl isothiocyanate (PEITC), a potential dietary cancer chemopreventive agent. Since PEITC inhibits NF-κB activation, air induction by this agent is consistent with the suppressive effect of NF-κB on air expression. This finding contributes a new clue to the role of NF-κB in regulating oxidative stress-induced pro-apoptotic genes and identifies a novel potential tool for enhancing pancreas cancer response to treatment., (Copyright © 2011 Wiley-Liss, Inc.)

BAG3, a member of the BAG co-chaperones family, is expressed in several cell types subjected to stressful conditions, such as exposure to high temperature, heavy metals, drugs. Furthermore, it is constitutively expressed in some tumors. Among the biological activities of the protein, there is apoptosis downmodulation; this appears to be exerted through BAG3 interaction with the heat shock protein (Hsp) 70, that influences cell apoptosis at several levels. We recently reported that BAG3 protein was detectable in the cytoplasm of reactive astrocytes in HIV-1-associated encephalopathy biopsies. Here we report that downmodulation of BAG3 protein levels allows caspase-3 activation by HIV-1 infection in human primary microglial cells. This is the first reported evidence of a role for BAG3 in the balance of death versus survival during viral infection., ((c) 2008 Wiley-Liss, Inc.)

BAG3 protein, a member of the BAG co-chaperones family, sustains cell survival, through its interaction with the heat shock protein (HSP) 70, in a variety of normal and neoplastic cell types. bag3 gene expression is induced by stressful stimuli. Here we report for the first time that two of the three putative heat shock-responsive elements (HSEs) in bag3 promoter interact with the heat shock factor (HSF) 1 in vitro and in vivo. Furthermore, downmodulation of HSF1 protein levels by specific small interfering (si) RNAs results in reducing BAG3 protein levels, indicating that the transcription factor plays a major role in bag3 gene expression. Because of the anti-apoptotic role of BAG3 protein, these results disclose a previously unrecognized pathway, through which HSF1 maintains cell survival., ((c) 2008 Wiley-Liss, Inc.)

A family of co-chaperone proteins that share the Bcl-2-associated athanogene (BAG) domain are involved in a number of cellular processes, including proliferation and apoptosis. Among these proteins, BAG3 has received increased attention due to its high levels in several disease models and ability to associate with Hsp70 and a number of other molecular partners. BAG3 expression is stimulated during cell response to stressful conditions, such as exposure to high temperature, heavy metals, and certain drugs. Here, we demonstrate that BAG3 expression is elevated upon HIV-1 infection of human lymphocytes and fetal microglial cells. Furthermore, BAG3 protein was detectable in the cytoplasm of reactive astrocytes in HIV-1-associated encephalopathy biopsies, suggesting that induction of BAG3 is part of the host cell response to viral infection. To assess the impact of BAG3 upregulation on HIV-1 gene expression, we performed transcription assays and demonstrated that BAG3 can suppress transcription of the HIV-1 long terminal repeat (LTR) in microglial cells. This activity was mapped to the kappaB motif of the HIV-1 LTR. Results from in vitro and in vivo binding assays revealed that BAG3 suppresses interaction of the p65 subunit of NF-kappaB with the kappaB DNA motif of the LTR. Results from binding and transcriptional assay identified the C-terminus of BAG3 as a potential domain involved in the observed inhibitory effect of BAG3 on p65 activity. These observations reveal a previously unrecognized cell response, that is, an increase in BAG3, elicited by HIV-1 infection, and may provide a new avenue for the suppression of HIV-1 gene expression., (Copyright 2006 Wiley-Liss, Inc.)