Tissue inhibitor of metalloproteinase-3 (TIMP3) promotes endothelial apoptosis via a caspase-independent mechanism
In this study, we examined the molecular mechanisms of TIMP3-mediated apoptosis in endothelial cells. We have previously demonstrated that mice developed smaller tumors with decreased vascularity when injected with breast carcinoma cells overexpressing TIMP3, than with control breast carcinoma cells. TIMP3 overexpression resulted in increased apoptosis in human breast carcinoma (MDA-MB435) in vivo but not in vitro. However, TIMP3 could induce apoptosis in ECs in vitro. The apoptotic activity of TIMP3 in ECs appears to be independent of MMP inhibitory activity. Furthermore, the equivalent expression of functional TIMP3 prom...
Source: Apoptosis - January 4, 2015 Category: Molecular Biology Source Type: research

Thy28 protects against anti-CD3-mediated thymic cell death in vivo
Abstract Apoptotic cell death plays a pivotal role in the development and/or maintenance of several tissues including thymus. Deregulated thymic cell death is associated with autoimmune diseases including experimental autoimmune encephalomyelitis (EAE), a prototype murine model for analysis of human multiple sclerosis. Because Thy28 expression is modulated during thymocyte development, we tested whether Thy28 affects induction of EAE as effectively as antigen-induced thymocyte deletion using Thy28 transgenic (TG) mice. Thy28 TG mice showed partial resistance to anti-CD3 monoclonal antibody (mAb)-induced thymic cel...
Source: Apoptosis - December 29, 2014 Category: Molecular Biology Source Type: research

Mycobacterium tuberculosis 38-kDa antigen induces endoplasmic reticulum stress-mediated apoptosis via toll-like receptor 2/4
In conclusion, MCPIP is important for host defense mechanisms in mycobacterial pathogenesis. (Source: Apoptosis)
Source: Apoptosis - December 28, 2014 Category: Molecular Biology Source Type: research

5-HT 2B receptor blockade attenuates β-adrenergic receptor-stimulated myocardial remodeling in rats via inhibiting apoptosis: role of MAPKs and HSPs
In conclusion, inhibition of apoptosis via modulation of MAPKs/HSPs is essential for 5-HT2BR blockade mediated cardioprotective effect. (Source: Apoptosis)
Source: Apoptosis - December 28, 2014 Category: Molecular Biology Source Type: research

Myofibrillogenesis regulator-1 attenuated hypoxia/reoxygenation-induced apoptosis by inhibiting the PERK/Nrf2 pathway in neonatal rat cardiomyocytes
Abstract The purpose of this study was to investigate the role of myofibrillogenesis regulator-1 (MR-1) in cardiomyocyte apoptosis induced by hypoxia/reoxygenation (H/R), through protein kinase R-like ER kinase (PERK)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. To address this aim, an H/R model of neonatal rat cardiomyocytes was used. MR-1 was overexpressed using an adenoviral vector system and knocked down using MR-1 specific siRNA. Apoptosis was assessed by using Annexin V/PI double staining, terminal deoxynucleotidyl transferase mediated dUTP-biotin nick end labeling assay, and the Bcl-2/Bax rat...
Source: Apoptosis - December 26, 2014 Category: Molecular Biology Source Type: research

Gamma-linolenic acid inhibits hepatic PAI-1 expression by inhibiting p38 MAPK-dependent activator protein and mitochondria-mediated apoptosis pathway
Abstract Fibrosis is induced by the excessive and abnormal deposition of extracellular matrix (ECM) with various growth factors in tissues. Transforming growth factor beta 1 (TGF-β1), plays a role in inducing apoptosis, modulates fibrosis, and ECM accumulation. Plasminogen activator inhibitor 1 (PAI-1) plays an important role in the development hepatic fibrosis. The overexpression of PAI-1 induces ECM accumulation, the main hallmark of chronic liver diseases. Death of hepatocytes is a characteristic feature of chronic liver disease due to various causes. The TGF-β1-mediated apoptotic pathway is regarded ...
Source: Apoptosis - December 23, 2014 Category: Molecular Biology Source Type: research

p27 kip1 overexpression regulates VEGF expression, cell proliferation and apoptosis in cell culture from eutopic endometrium of women with endometriosis
Abstract We hypothesized that p27kip1 overexpression can regulate endometriosis cell proliferation, apoptosis and vascular endothelial growth factor (VEGF) expression in the endometrium. The overexpression of p27kip1 was obtained by transduction of p27kip1 in primary cultures of endometrium obtained from women with endometriosis tissue with gene therapy technology. First generation bicistronic adenovirus: AdCMVhp27IRESEGFP (Adp27) and AdCMVNull (AdNull) were engineered in order to induce p27kip1 expression in endometrial cells primary culture. The effect of p27kip1 overexpression was elucidated through the cell pr...
Source: Apoptosis - December 23, 2014 Category: Molecular Biology Source Type: research

Hijacking of death receptor signaling by bacterial pathogen effectors
Abstract Death receptors such as Tumor necrosis factor receptor 1, FAS and TNF-associated apoptosis-inducing ligand-R1/2 play a major role in counteracting with bacterial pathogen infection through regulation of inflammation and programmed cell death. The highly regulated death receptor signaling is frequently targeted by gram-negative bacterial pathogens such as Salmonella, Shigella, enteropathogenic Escherichia coli and enterohamorrhagic Escherichia coli, which harbor a conserved type III secretion system that delivers a repertoire of effector proteins to manipulate host signal transductions for their own benefi...
Source: Apoptosis - December 21, 2014 Category: Molecular Biology Source Type: research

FOXO3-mediated up-regulation of Bim contributes to rhein-induced cancer cell apoptosis
Abstract The anthraquinone compound rhein is a natural agent in the traditional Chinese medicine rhubarb. Preclinical studies demonstrate that rhein has anticancer activity. Treatment of a variety of cancer cells with rhein may induce apoptosis. Here, we report that rhein induces atypical unfolded protein response in breast cancer MCF-7 cells and hepatoma HepG2 cells. Rhein induces CHOP expression, eIF2α phosphorylation and caspase cleavage, while it does not induce glucose-regulated protein 78 (GRP78) expression in both MCF-7 and HepG2 cells. Meanwhile, rhein inhibits thapsigargin-induced GRP78 expression a...
Source: Apoptosis - December 12, 2014 Category: Molecular Biology Source Type: research

Structural insight into CIDE domains: the Janus face of CIDEs
Abstract Cell-death inducing DFF45-like effect domain (CIDE domain) is a protein interaction module that was initially found in DNA fragmentation factor (DFF) proteins DFF40 and DFF45. Several other CIDE-containing proteins, CIDE-A, CIDE-B, and CIDE-3, have since been identified in humans. Although the main function of these proteins is associated with apoptosis, recent studies have identified roles of CIDE-containing proteins in energy metabolism, especially involvement in control of the size of lipid droplets. Because CIDE-containing proteins perform critical tasks in apoptosis and energy metabolism and have bee...
Source: Apoptosis - December 9, 2014 Category: Molecular Biology Source Type: research

An updated view on the structure and function of PYRIN domains
Abstract The PYRIN domain (PYD) is a protein–protein interaction domain, which belongs to the death domain fold (DDF) superfamily. It is best known for its signaling function in innate immune responses and particularly in the assembly of inflammasomes, which are large protein complexes that allow the induced proximity-mediated activation of caspase-1 and subsequently the release of pro-inflammatory cytokines. The molecular mechanism of inflammasome assembly was only recently elucidated and specifically requires PYD oligomerization. Here we discuss the recent advances in our understanding of PYD signaling and...
Source: Apoptosis - December 1, 2014 Category: Molecular Biology Source Type: research

Neuroprotective effects of three different sizes nanochelating based nano complexes in MPP(+) induced neurotoxicity
Abstract Parkinson’s disease (PD) is the world’s second most common dementia, which the drugs available for its treatment have not had effects beyond slowing the disease process. Recently nanotechnology has induced the chance for designing and manufacturing new medicines for neurodegenerative disease. It is demonstrated that by tuning the size of a nanoparticle, the physiological effect of the nanoparticle can be controlled. Using novel nanochelating technology, three nano complexes: Pas (150 nm), Paf (100 nm) and Pac (40 nm) were designed and in the present study their neuroprotective e...
Source: Apoptosis - December 1, 2014 Category: Molecular Biology Source Type: research

Structure and function of Toll/interleukin-1 receptor/resistance protein (TIR) domains
Abstract The Toll/interleukin-1 receptor/resistance protein (TIR) domain is a protein–protein interaction domain consisting of 125–200 residues, widely distributed in animals, plants and bacteria but absent from fungi, archea and viruses. In plants and animals, these domains are found in proteins with functions in innate immune pathways, while in bacteria, some TIR domain-containing proteins interfere with the innate immune pathways in the host. TIR domains function as protein scaffolds, mostly involving self-association and homotypic interactions with other TIR domains. In the last 15 years, the ...
Source: Apoptosis - December 1, 2014 Category: Molecular Biology Source Type: research

Death effecter domain for the assembly of death-inducing signaling complex
Abstract Death-inducing signaling complex (DISC) is a platform for the activation of initiator caspase in extrinsic apoptosis. Assembly of DISC is accomplished by two different types of homotypic interaction: one is between death domains (DDs) of a death receptor and FADD, and the other is between death effecter domains (DEDs) of FADD, procaspase-8/-10 and cFLIP. Recent biochemical investigations on the stoichiometry of DISC have revealed that single-DED-containing FADD exists in DISC in a substantially lower abundance than the sum of tandem-DEDs-containing components that are procaspase-8 and cFLIP. In addition, ...
Source: Apoptosis - December 1, 2014 Category: Molecular Biology Source Type: research

Structural basis of cell apoptosis and necrosis in TNFR signaling
Abstract The tumor necrosis factor receptors (TNFRs) play essential roles in innate and adaptive immunity. Depending on conditions, TNFR induces multiple cell fates including cell survival, cell apoptosis, and cell programmed necrosis. Here, we review recent progress in structural studies of the TNFR signaling pathway. The structural basis for the high order signal complexes, including the DISC, ripoptosome, necrosome, and RIP3/MLKL complex, may provide novel insights for understanding the biophysical principles of cell signaling cascades. (Source: Apoptosis)
Source: Apoptosis - December 1, 2014 Category: Molecular Biology Source Type: research

Pro-apoptotic gene regulation and its activation by gamma-irradiation in the Caribbean fruit fly, Anastrepha suspensa
In this study, we determined the developmental profiles of Asrpr and Ashid transcripts during embryogenesis and in embryos exposed to γ-irradiation. Transcript levels of both genes determined by qRT-PCR were low throughout embryogenesis, with strong Ashid expression occurring during early to mid-embryogenesis and Asrpr expression peaking in late embryogenesis. This correlated to acridine orange stained apoptotic cells first appearing at 17 h and increasing over time. However, when irradiated at 16 h post-oviposition embryos exhibited significant levels of apoptosis consistent with strong induction of Asrpr ...
Source: Apoptosis - November 30, 2014 Category: Molecular Biology Source Type: research

Apoptosis imaging studies in various animal models using radio-iodinated peptide
In this study, we radiolabeled the recently identified histone H1 targeting peptide (ApoPep-1) and evaluated its potential as a new apoptosis imaging agent in various animal models. ApoPep-1 (CQRPPR) was synthesized, and an extra tyrosine residue was added to its N-terminal end for radiolabeling. This peptide was radiolabeled with 124I and 131I and was tested for its serum stability. Surgery- and drug-induced apoptotic rat models were prepared for apoptosis evaluation, and PET imaging was performed. Doxorubicin was used for xenograft tumor treatment in mice, and the induced apoptosis was studied. Tumor metabolism and proli...
Source: Apoptosis - November 28, 2014 Category: Molecular Biology Source Type: research

mTOR ATP-competitive inhibitor INK128 inhibits neuroblastoma growth via blocking mTORC signaling
In conclusion, we have shown that INK128-mediated mTOR inhibition possessed substantial antitumor activity and could significantly increase the sensitivity of neuroblastoma cells to Dox therapy. Taken together, our results indicate that using INK128 can provide additional efficacy to current chemotherapeutic regimens and represent a new paradigm in restoring drug sensitivity in neuroblastoma. (Source: Apoptosis)
Source: Apoptosis - November 26, 2014 Category: Molecular Biology Source Type: research

The versatile roles of CARDs in regulating apoptosis, inflammation, and NF-κB signaling
Abstract CARD subfamily is the second largest subfamily in the DD superfamily that plays important roles in regulating various signaling pathways, including but not limited to NF-kB activation signaling, apoptosis signaling and inflammatory signaling. The CARD subfamily contains 33 human CARD-containing proteins, regulating the assembly of many signaling complexes, including apoptosome, inflammsome, nodosome, the CBM complex, PIDDosome, the TRAF2 complex, and the MAVS signalosome, by homotypic CARD–CARD interactions. The mechanism of how CARDs find the right binding partner to form a specific complex remains...
Source: Apoptosis - November 24, 2014 Category: Molecular Biology Source Type: research

MiR-218-targeting-Bmi-1 mediates the suppressive effect of 1,6,7-trihydroxyxanthone on liver cancer cells
In conclusion, THA might be a potential anti-cancer drug candidate, at least in part, through the activation of miR-218 and suppression of Bmi-1 expression. (Source: Apoptosis)
Source: Apoptosis - November 21, 2014 Category: Molecular Biology Source Type: research

TSPO ligand residence time influences human glioblastoma multiforme cell death/life balance
Abstract Ligands addressed to the mitochondrial Translocator Protein (TSPO) have been suggested as cell death/life and steroidogenesis modulators. Thus, TSPO ligands have been proposed as drug candidates in several diseases; nevertheless, a correlation between their binding affinity and in vitro efficacy has not been demonstrated yet, questioning the specificity of the observed effects. Since drug-target residence time is an emerging parameter able to influence drug pharmacological features, herein, the interaction between TSPO and irDE-MPIGA, a covalent TSPO ligand, was investigated in order to explore TSPO contr...
Source: Apoptosis - November 20, 2014 Category: Molecular Biology Source Type: research

The Bcl-2 family: structures, interactions and targets for drug discovery
Abstract Two phylogenetically and structurally distinct groups of proteins regulate stress induced intrinsic apoptosis, the programmed disassembly of cells. Together they form the B cell lymphoma-2 (Bcl-2) family. Bcl-2 proteins appeared early in metazoan evolution and are identified by the presence of up to four short conserved sequence blocks known as Bcl-2 homology (BH) motifs, or domains. The simple BH3-only proteins bear only a BH3-motif and are intrinsically disordered proteins and antagonize or activate the other group, the multi-motif Bcl-2 proteins that have up to four BH motifs, BH1-BH4. Multi-motif Bcl-...
Source: Apoptosis - November 15, 2014 Category: Molecular Biology Source Type: research

Apoptosis for prediction of radiotherapy late toxicity: lymphocyte subset sensitivity and potential effect of TP53 Arg72Pro polymorphism
Abstract We tested apoptosis levels in in vitro irradiated T-lymphocytes from breast cancer (BC) patients with radiotherapy-induced late effects. Previous results reported in the literature were revised. We also examined the effect of TP53 Arg72Pro polymorphism on irradiation-induced apoptosis (IA). Twenty BC patients, ten with fibrosis and/or telangiectasias and ten matched controls with no late reactions, were selected from those receiving radiotherapy between 1993 and 2007. All patients were followed-up at least 6 years after radiotherapy. Using the combination of both CD3 and CD8 antibodies the in vitro I...
Source: Apoptosis - November 15, 2014 Category: Molecular Biology Source Type: research

RIP1-dependent Bid cleavage mediates TNFα-induced but Caspase-3-independent cell death in L929 fibroblastoma cells
Abstract L929 fibroblastoma cells (L929-A) and L929 fibrosarcoma cells (L929-N) are different cell lines that are commonly used to study the cytotoxicity of tumor necrosis factor alpha (TNFα). TNFα has been reported to induce necrosis in both of these cell lines. However, comparing the TNFα-induced cell death in these two cell lines, we found that, unlike the L929-N cells that show typical RIP3-dependent necrosis, TNFα-induced cell death in L929-A cells is pan-caspase inhibitor Z-VAD-FMK (Z-VAD)-sensitive, which does not depend on RIP3. We also confirmed that the cell death signal in the L9...
Source: Apoptosis - November 15, 2014 Category: Molecular Biology Source Type: research

Oxidative stress by monosodium urate crystals promotes renal cell apoptosis through mitochondrial caspase-dependent pathway in human embryonic kidney 293 cells: mechanism for urate-induced nephropathy
Abstract The aim of this study is to clarify the effect of oxidative stress on monosodium urate (MSU)-mediated apoptosis of renal cells. Quantitative real-time polymerase chain reaction and immunoblotting for Bcl-2, caspase-9, caspase-3, iNOS, cyclooxygenase-2 (COX-2), interleukin-1β (IL-1β), IL-18, TNF receptor-associated factor-6 (TRAF-6), and mitogen-activated protein kinases were performed on human embryonic kidney 293 (HEK293) cells, which were stimulated by MSU crystals. Fluorescence-activated cell sorting was performed using annexin V for assessment of apoptosis. Reactive oxygen species (ROS) were...
Source: Apoptosis - November 15, 2014 Category: Molecular Biology Source Type: research

Tandem DEDs and CARDs suggest novel mechanisms of signaling complex assembly
Abstract Apoptosis is an important process to maintain cellular homeostasis. Deregulated apoptosis has linked to a number of diseases, such as inflammatory diseases, neurodegenerative disorder, and cancers. A major signaling complex in the death receptor signaling pathway leading to apoptosis is death-induced signaling complex (DISC), which is regulated mainly by death effector domain (DED)-containing proteins. There are seven DED-containing proteins in human, including FADD, c-FLIP, caspase-8, caspase-10, DEDD, DEDD2, and PEA-15. The main players in DISC formation employ tandem DEDs for regulating signaling compl...
Source: Apoptosis - November 15, 2014 Category: Molecular Biology Source Type: research

Activation and assembly of the inflammasomes through conserved protein domain families
Abstract Inflammasomes are oligomeric protein complexes assembled through interactions among the death domain superfamily members, in particular the CARD and PYD domains. Recent progress has shed lights on how the ASC PYD can polymerize to form filaments using multiple domain:domain interfaces, and how the caspase4 CARD can recognize LPS to activate the non-classical inflammasome pathway. Comprehensive understanding of the molecular mechanisms of inflammasome activation and assembly require more extensive structural and biophysical dissection of the inflammasome components and complexes, in particular additional C...
Source: Apoptosis - November 15, 2014 Category: Molecular Biology Source Type: research

BIGH3 protein and macrophages in retinal endothelial cell apoptosis
Abstract Diabetes is a pandemic disease with a higher occurrence in minority populations. The molecular mechanism to initiate diabetes-associated retinal angiogenesis remains largely unknown. We propose an inflammatory pathway of diabetic retinopathy in which macrophages in the diabetic eye provide TGFβ to retinal endothelial cells (REC) in the retinal microvasculature. In response to TGFβ, REC synthesize and secrete a pro-apoptotic BIGH3 (TGFβ-Induced Gene Human Clone 3) protein, which acts in an autocrine loop to induce REC apoptosis. Rhesus monkey retinal endothelial cells (RhREC) were treated wi...
Source: Apoptosis - November 7, 2014 Category: Molecular Biology Source Type: research

The domains of apoptosis and inflammation
(Source: Apoptosis)
Source: Apoptosis - October 30, 2014 Category: Molecular Biology Source Type: research

Glycolytic enzyme upregulation and numbness of mitochondrial activity characterize the early phase of apoptosis in cerebellar granule cells
In conclusion, the data propose that both aerobic, i.e. Warburg effect, essentially due to the protective numbness of mitochondria, and anaerobic glycolysis, rather due to the mitochondrial impairment, characterize the entire time frame of apoptosis, from the early to the late phase, which mimics the development of AD. (Source: Apoptosis)
Source: Apoptosis - October 29, 2014 Category: Molecular Biology Source Type: research

Dichloroacetate affects proliferation but not survival of human colorectal cancer cells
Abstract Dichloroacetate (DCA) is a metabolic reprogramming agent that reverses the Warburg effect, causing cancer cells to couple glycolysis to oxidative phosphorylation. This has been shown to induce apoptosis and reduce the growth of various types of cancer but not normal cells. Colorectal cancer cells HCT116, HCT116 p53−/−, and HCT116 Bax−/−, were treated with DCA in vitro. Response to treatment was determined by measuring PDH phosphorylation, apoptosis, proliferation, and cell cycle. Molecular changes associated with these responses were determined using western immunoblotting and quan...
Source: Apoptosis - October 26, 2014 Category: Molecular Biology Source Type: research

Pifithrin-α provides neuroprotective effects at the level of mitochondria independently of p53 inhibition
Abstract Impaired mitochondrial integrity and function are key features of intrinsic death pathways in neuronal cells. Therefore, key regulators of intrinsic death pathways acting upstream of mitochondria are potential targets for therapeutic approaches of neuroprotection. The tumor suppressor p53 is a well-established regulator of cellular responses towards different kinds of lethal stress, including oxidative stress. Recent reports suggested that p53 may affect mitochondrial integrity and function through both, transcriptional activation of mitochondria-targeted pro-death proteins and direct effects at the mitoc...
Source: Apoptosis - October 24, 2014 Category: Molecular Biology Source Type: research

Inhibition of VDAC1 prevents Ca 2+ -mediated oxidative stress and apoptosis induced by 5-aminolevulinic acid mediated sonodynamic therapy in THP-1 macrophages
Abstract Ultrasound combined with endogenous protoporphyrin IX derived from 5-aminolevulinic acid (ALA-SDT) is known to induce apoptosis in multiple cancer cells and macrophages. Persistent retention of macrophages in the plaque has been implicated in the pathophysiology and progression of atherosclerosis. Here we investigated the effects of inhibition of voltage-dependent anion channel 1 (VDAC1) on ALA-SDT-induced THP-1 macrophages apoptosis. Cells were pre-treated with VDAC1 inhibitor 4,4′-diisothiocyanostilbene-2,2′-disulfonic acid (DIDS) disodium salt for 1 h or downregulated VDAC1 expression ...
Source: Apoptosis - October 23, 2014 Category: Molecular Biology Source Type: research

Nanosecond pulsed electric fields modulate the expression of Fas/CD95 death receptor pathway regulators in U937 and Jurkat Cells
Abstract In this publication, we demonstrate that exposure of Jurkat and U937 cells to nanosecond pulsed electrical fields (nsPEF) can modulate the extrinsic-mediated apoptotic pathway via the Fas/CD95 death receptor. An inherent difference in survival between these two cell lines in response to 10 ns exposures has been previously reported (Jurkat being more sensitive to nsPEF than U937), but the reason for this sensitivity difference remains unknown. We found that exposure of each cell line to 100, 10 ns pulses at 50 kV/cm caused a marked increase in expression of cFLIP (extrinsic apoptosis inhibit...
Source: Apoptosis - October 21, 2014 Category: Molecular Biology Source Type: research

Elatoside C protects against hypoxia/reoxygenation-induced apoptosis in H9c2 cardiomyocytes through the reduction of endoplasmic reticulum stress partially depending on STAT3 activation
This study aimed to investigate the possible protective effect of Elatoside C against hypoxia/reoxygenation (H/R)-induced H9c2 cardiomyocyte injury and its underlying mechanisms. H9c2 cardiomyocytes were subjected to H/R in the presence of Elatoside C. Our results showed that Elatoside C (25 μM) treatment provided significant protection against H/R-induced cell death, as evidenced by improved cell viability, maintained mitochondrial membrane potential, diminished mitochondrial ROS, and reduced apoptotic cardiomyocytes (P 
Source: Apoptosis - October 18, 2014 Category: Molecular Biology Source Type: research

Role of Bcl-xL/Beclin-1 in synergistic apoptotic effects of secretory TRAIL-armed adenovirus in combination with mitomycin C and hyperthermia on colon cancer cells
In this study, we attempted to develop a multimodality approach using chemotherapeutic agent mitomycin C, biologic agent tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo-2L), and mild hyperthermia to treat colon cancer. For this study, human colon cancer LS174T, LS180, HCT116 and CX-1 cells were infected with secretory TRAIL-armed adenovirus (Ad.TRAIL) and treated with chemotherapeutic agent mitomycin C and hyperthermia. The combinatorial treatment caused a synergistic induction of apoptosis which was mediated through an increase in caspase activation. The combinational treatment promoted the JNK-Bcl-xL-B...
Source: Apoptosis - October 14, 2014 Category: Molecular Biology Source Type: research

The serine protease inhibitor TLCK attenuates intrinsic death pathways in neurons upstream of mitochondrial demise
Abstract It is well-established that activation of proteases, such as caspases, calpains and cathepsins are essential components in signaling pathways of programmed cell death (PCD). Although these proteases have also been linked to mechanisms of neuronal cell death, they are dispensable in paradigms of intrinsic death pathways, e.g. induced by oxidative stress. However, emerging evidence implicated a particular role for serine proteases in mechanisms of PCD in neurons. Here, we investigated the role of trypsin-like serine proteases in a model of glutamate toxicity in HT-22 cells. In these cells glutamate induces...
Source: Apoptosis - October 14, 2014 Category: Molecular Biology Source Type: research

Gamma secretase inhibitors enhance vincristine-induced apoptosis in T-ALL in a NOTCH-independent manner
We examined whether GSI could enhance the cytotoxic effect of anti-leukemic agents in the GSI-resistant T-ALL cells although GSI does not have anti-tumor effect as a single agent. GSI significantly increased cell death induced by Vincristine (VCR) but not other anti-leukemic drugs (Methotrexate, Asparaginase, and Cytarabine). The GSI effect in enhancing VCR efficacy was not the result of inhibition of Notch signaling. GSI augmented VCR-induced mitotic arrest, followed by apoptosis. GSI accelerated VCR-triggered loss of mitochondrial membrane potential and caspase-mediated apoptosis. Our finding suggests that GSI has other ...
Source: Apoptosis - October 14, 2014 Category: Molecular Biology Source Type: research

DNA methylation of apoptosis genes in rectal cancer predicts patient survival and tumor recurrence
Abstract Deregulation of the apoptotic pathway, one of the hallmarks of tumor growth and -progression, has been shown to have prognostic value for tumor recurrence in rectal cancer. In order to develop clinically relevant biomarkers, we studied the methylation status of promoter regions of key apoptosis genes in rectal cancer patients, using methylation-sensitive restriction enzymes. DNA was extracted from fresh-frozen tumor tissues of 49 stage I-III rectal cancer patients and 10 normal rectal tissues. The results of this pilot study were validated in 88 stage III tumor tissues and 18 normal rectal tissues. We fo...
Source: Apoptosis - October 14, 2014 Category: Molecular Biology Source Type: research

XI-011 enhances cisplatin-induced apoptosis by functional restoration of p53 in head and neck cancer
Abstract Head and neck cancer (HNC), one of the most common cancers worldwide, frequently involves mutation of the TP53 gene and dysregulation of the p53 pathway. Overexpression of MDM2 or MDM4 inactivates the tumor-suppressive function of p53. Restoration of p53 function that counteracts these p53 repressors can lead to in vivo tumor regression. Therefore, the present study assessed the ability of the small molecule p53 activator XI-011 (NSC146109) to induce apoptosis in HNC by restoring p53 function. We tested the effects of XI-011 treatment in HNC cell lines, either individually or in combination with cisplati...
Source: Apoptosis - October 14, 2014 Category: Molecular Biology Source Type: research

A novel oxaliplatin derivative, Ht-2, triggers mitochondrion-dependent apoptosis in human colon cancer cells
Abstract Ht-2 is a novel oxaliplatin derivative previously identified in a compound screen performed by our laboratory. In the present study, we evaluated the antitumor effects of Ht-2 and investigated its underlying mechanism of action. Ht-2 exhibited anti-tumor activity and demonstrated low cytotoxicity in normal cells in vitro. The IC50 of Ht-2 was 2–10-fold lower than oxaliplatin in all of the cancer cell lines tested except MCF-7 cells, whereas, the value was threefold higher than cisplatin or oxaliplatin in normal HUVEC cells. Further studies indicated that Ht-2 caused S-phase arrest and led to apo...
Source: Apoptosis - October 12, 2014 Category: Molecular Biology Source Type: research

Effect of PKCα expression on Bcl-2 phosphorylation and cell death by hypericin
Abstract In order to explain the contribution of the protein kinase Cα (PKCα) in apoptosis induced by photo-activation of hypericin (Hyp), a small interfering RNA was used for post-transcriptional silencing of pkcα gene expression. We have evaluated the influence of Hyp photo-activation on cell death in non-transfected and transfected (PKCα−) human glioma cells (U-87 MG). No significant differences were detected in cell survival between non-transfected and transfected PKCα− cells. However, the type of cell death was notably affected by silencing the pkcα gene. Ph...
Source: Apoptosis - October 9, 2014 Category: Molecular Biology Source Type: research

Glucotoxic and diabetic conditions induce caspase 6-mediated degradation of nuclear lamin A in human islets, rodent islets and INS-1 832/13 cells
Abstract Nuclear lamins form the lamina on the interior surface of the nuclear envelope, and regulate nuclear metabolic events, including DNA replication and organization of chromatin. The current study is aimed at understanding the role of executioner caspase 6 on lamin A integrity in islet β-cells under duress of glucotoxic (20 mM glucose; 24 h) and diabetic conditions. Under glucotoxic conditions, glucose-stimulated insulin secretion and metabolic cell viability were significantly attenuated in INS-1 832/13 cells. Further, exposure of normal human islets, rat islets and INS-1 832/13 cells to ...
Source: Apoptosis - October 8, 2014 Category: Molecular Biology Source Type: research

Chromatin status of apoptosis genes correlates with sensitivity to chemo-, immune- and radiation therapy in colorectal cancer cell lines
In conclusion, the results presented in this study indicate that the balance between activating and silencing histone modifications, reflecting the chromatin status of apoptosis genes, can be used to predict the response of tumor cells to different anti-cancer therapies and could provide a novel target to sensitize tumors to obtain adequate treatment responses. (Source: Apoptosis)
Source: Apoptosis - October 8, 2014 Category: Molecular Biology Source Type: research

Enhanced glycogen synthase kinase-3β activity mediates podocyte apoptosis under diabetic conditions
This study was undertaken to examine the changes in GSK-3β activity in podocytes under diabetic conditions and to elucidate the functional role of GSK-3β in podocyte apoptosis. In vivo, 32 rats were injected with either diluent (n = 16, C) or with streptozotocin intraperitoneally (n = 16, DM), and 8 rats from each group were treated with 6-bromoindirubin-3′-oxime (BIO) for 3 months. In vitro, immortalized mouse podocytes were exposed to 5.6 mM glucose or 30 mM glucose (HG) with or without 10 μM BIO. Western blot analysis and TUNEL or Hoechst 33342 staining were per...
Source: Apoptosis - October 5, 2014 Category: Molecular Biology Source Type: research

Radiation-induced glioblastoma signaling cascade regulates viability, apoptosis and differentiation of neural stem cells (NSC)
In this study, we have evaluated the effects of irradiated glioblastoma cells on viability, proliferation and differentiation potential of non-irradiated (bystander) NSC through radiation-induced signaling cascades. Using media transfer experiments, we demonstrated significant effects of the U87MG glioblastoma secretome after gamma-irradiation on apoptosis in non-irradiated NSC. Addition of anti-TRAIL antibody to the transferred media partially suppressed apoptosis in NSC. Furthermore, we observed a dramatic increase in the production and secretion of IL8, TGFβ1 and IL6 by irradiated glioblastoma cells, which could pr...
Source: Apoptosis - October 1, 2014 Category: Molecular Biology Source Type: research

Interferon-β counter-regulates its own pro-apoptotic action by activating p38 MAPK signalling in human SH-SY5Y neuroblastoma cells
Abstract Type I interferons (IFNs) induce apoptosis of neuroblastoma cells, but the molecular mechanisms regulating this event have not been completely elucidated. Here, we investigated the role of p38 mitogen activated protein kinase (MAPK) activity, a key regulator of apoptosis and a known modulator of IFN-induced responses in non-neuronal cells. We show that in SH-SY5Y human neuroblastoma cells IFN-β induced a delayed and sustained increase of p38 MAPK activity through a novel mechanism involving the sequential activation of Janus kinase-signal transducer and activator of transcription-1 signalling, enhan...
Source: Apoptosis - September 25, 2014 Category: Molecular Biology Source Type: research

Urokinase-type plasminogen activator receptor regulates apoptotic sensitivity of colon cancer HCT116 cell line to TRAIL via JNK-p53 pathway
In this study, we investigated whether uPAR could modulate TRAIL-induced apoptosis in human colon cancer cells HCT116. Using an antisense strategy, we established a stable HCT116 cell line with down-regulated uPAR. The sensitivity to TRAIL-induced apoptosis was evaluated by FACS analysis. Our results show that the inhibition of uPAR could sensitize HCT116 to TRAIL-induced apoptosis. uPAR inhibition changed the expression of mitochondrial apoptotic pathway proteins, including Bcl-2, Bax, Bid and p53, in a pro-apoptotic manner. We also found that the inhibition of uPAR down-regulated the phosphorylation of FAK, ERK and JNK. ...
Source: Apoptosis - September 25, 2014 Category: Molecular Biology Source Type: research

Drosophila p53 controls Notch expression and balances apoptosis and proliferation
We present evidence that simultaneous reduction of Dp53 and Notch function synergistically increases the wing phenotype of Notch heterozygous mutant flies. Further, we found that a Notch cis-regulatory element is responsive to loss and gain of Dp53 function and that over-expression of Dp53 up-regulates Notch mRNA and protein expression. These findings suggest not only that Dp53 and Notch act together to control wing development but also indicate that Dp53 transcriptionally regulates Notch expression. Moreover, using Notch  gain and loss of function mutations we examined the relevance of Dp53 and Notch inter...
Source: Apoptosis - September 25, 2014 Category: Molecular Biology Source Type: research

The drosophila Bcl-2 family protein Debcl is targeted to the proteasome by the β-TrCP homologue slimb
Abstract The ubiquitin–proteasome system is one of the main proteolytic pathways. It inhibits apoptosis by degrading pro-apoptotic regulators, such as caspases or the tumor suppressor p53. However, it also stimulates cell death by degrading pro-survival regulators, including IAPs. In Drosophila, the control of apoptosis by Bcl-2 family members is poorly documented. Using a genetic modifier screen designed to identify regulators of mammalian bax-induced apoptosis in Drosophila, we identified the ubiquitin activating enzyme Uba1 as a suppressor of bax-induced cell death. We then demonstrated that Uba1 also re...
Source: Apoptosis - September 25, 2014 Category: Molecular Biology Source Type: research