Proteasome inhibitors exhibit antitumor activity against malignancies of different histology. Yet, the mechanisms underlying this effect are poorly understood. Recent evidence indicates that antiapoptotic factors may also accumulate as a consequence of exposure to these drugs, possibly reducing their cytotoxicity. These include the Bcl-2 family member Mcl-1, whose down-regulation has ...

Topoisomerase I inhibitors are effective anticancer therapies and have shown activity in hematologic malignancies. Here we show for the first time that SN38, the potent active metabolite of irinotecan, induces c-Jun NH(2)-terminal kinase activation, Fas up-regulation, and caspase 8-mediated apoptosis in multiple myeloma (MM) cells. Proteasomal degradation of nuclear topoisomerase ...

BACKGROUND: Cisplatin is a commonly used chemotherapeutic agent which causes apoptosis or necrosis of renal tubular epithelial cells in vitro. Caspases are a family of cysteine proteases that mediate apoptosis (caspase-3) and inflammation (caspase-1). Although well studied in vitro, caspases have not been previously studied in cisplatin-induced acute renal failure ...

Androgen has been implicated as a negative regulator of host immune function and a factor contributing to the gender dimorphism of autoimmunity. Conversely, androgen deprivation has been suggested to potentiate male host immunity. Studies have shown that removal of androgen in postpubertal male mice produces an increase in size and ...

This review on normal and neoplastic growth of the prostate emphasizes the importance of epithelial-mesenchymal/stromal interactions. Accordingly, during prostatic development urogenital sinus mesenchyme (a) specifies prostatic epithelial identity, (b) induces epithelial bud formation, (c) elicits prostatic bud growth and regulates ductal branching, (d) promotes differentiation of a secretory epithelium, and ...

OBJECTIVES: The histone deacetylase inhibitor suberoylanilide hydroxamic acid induces apoptosis in some malignancies through mitochondrial injury and generation of reactive oxygen species. Histone deacetylase inhibitors also activate the antiapoptotic transcription factor nuclear factor kappaB. We hypothesize that proteasome inhibition with bortezomib (Velcade; Millennium Pharmaceuticals, Inc, Cambridge, Mass)will inhibit nuclear factor ...

PURPOSE: Symptomatic benign prostatic hyperplasia (BPH) is one of the most common ailments seen by the urologist. Significant advances have occurred in medical and surgical therapy, and in the understanding of the biology of this disease. However, the basic science literature is often conflicting and confusing, without a unified voice. ...

BACKGROUND AND AIMS: The extent and severity of mucosal injury in inflammatory bowel diseases are determined by the disequilibrium between 2 opposing processes: reparative and cytoprotective mechanisms vs. inflammation-induced injury. Probiotics may provide clinical benefit by ameliorating colitis; however, their mechanisms of action remain largely unknown. Our objective was to ...

The ubiquitin proteasome pathway is the major mechanism used by eukaryotic cells for degradation of proteins. Bortezomib, a highly potent and specific inhibitor of the proteasome, has been demonstrated to have activity against multiple myeloma as a single agent in phase I and II clinical trials. Modulation of proteasome function ...

The purpose of the present study is to investigate the role of X-linked inhibitor of apoptosis protein (XIAP) in the regulation of apoptosis induced by cisplatin in human prostate cancer cell line (LNCaP). We examined the effects of cisplatin on cell growth and apoptosis in LNCaP by 2-(4-lodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium salt ...

BACKGROUND: Reduced apoptosis of neutrophil granulocytes (PMN) contributes to pathogenesis of systemic inflammatory response syndrome, sepsis, and multiple organ dysfunction syndrome. The intracellular inhibitor of apoptosis proteins has been shown to inhibit activated caspase-3. We investigated the turnover dynamics of cIAP-2 mRNA and caspase-3 protein in a neutrophil ex vivo ...

The experimentally induced cryptorchid mouse model is useful for elucidating the in vivo molecular mechanism of germ cell apoptosis. Apoptosis, in general, is thought to be partly regulated by the ubiquitin-proteasome system. Here, we analyzed the function of two closely related members of the ubiquitin C-terminal hydrolase (UCH) family in ...

The elucidation of detailed new signaling pathways in normal cells and how their perturbation contributes to the development of the malignant phenotype has created innumerable venues for the development of novel drugs that can affect these targets in therapeutically meaningful ways. For example, our understanding of the complex biology underlying ...

The ubiquitin-proteasome pathway has a central role in selective degradation of intracellular proteins. Among the key proteins degraded by the system are those involved in the control of inflammation, cell cycle regulation and gene expression. With numerous important cellular pathways affected, derangements in the ubiquitin system were shown to result ...

PURPOSE: The purpose of this study was to examine interactions between the proteasome inhibitor bortezomib (Velcade) and the histone deacetylase (HDAC) inhibitors sodium butyrate and suberoylanilide hydroxamic acid in human multiple myeloma (MM) cells that are sensitive and resistant to conventional agents. EXPERIMENTAL DESIGN: MM cells were exposed to bortezomib ...

The molecular chaperones are housekeeping molecules that assist in the folding and prevention of the aggregation of proteins and nucleotides, as well as participating in the elimination of ubiquitinated molecules. Evidence is reviewed to suggest that the Werner protein is a DNA chaperone and also that an increase in the ...

Graft-versus-host disease (GVHD) represents a major hurdle impeding the efficacy of allogeneic bone marrow transplantation (BMT). Bortezomib is a proteasome inhibitor that was recently approved for treatment of myeloma. We found that bortezomib potently inhibited in vitro mixed lymphocyte responses and promoted the apoptosis of alloreactive T cells. Bortezomib given ...

Proteasome inhibitors, like MG132, can exert cell growth inhibitory and apoptotic effects in different tumor types. The apoptotic mechanism of these compounds involves the activation of the effector caspases. beta-catenin, also an oncogene, represents one of the substrates of these proteases, but the consequences of its cleavage are poorly understood. ...

The ubiquitin-proteasome pathway plays a central role in the targeted destruction of cellular proteins, including cell cycle regulatory proteins. Because these pathways are critical for the proliferation and survival of all cells, and in particular cancerous cells, proteasome inhibition is a potentially attractive anticancer therapy. Based on encouraging cytotoxic activity, ...

The anticancer drug cisplatin induces cell death by apoptosis. Apoptosis is dependent on cellular loss of potassium ions (K+). We have recently shown that the antifungal drug amphotericin B (enhancing K+ efflux), combined with the Na+, K+, 2Cl(-)-cotransport blocker bumetanide (decreasing K+ influx), augmented cisplatin-induced apoptosis in vitro. We therefore ...

Human papilloma viruses (HPVs) are small double-stranded DNA viruses that infect mucosal and cutaneous epithelium and induce cervical cancer. It has been shown that interferon (IFN)gamma suppresses proliferation of HPV-infected cells by suppressing expression of HPV E7. Here, we found that IFNgamma induces not only suppression of E7 transcription but ...

In utero exposure of male C57BL/6 mice to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) prevents prostatic epithelial buds from forming in the ventral region of the urogenital sinus (UGS) and reduces the number of buds that form in the dorsolateral region. This inhibition of budding is aryl hydrocarbon receptor (AHR) dependent and appears to ...

BACKGROUND: Apoptotic propensity is currently viewed as an important parameter in drug-induced toxicity. But other cell death pathways exist e.g. micronucleation, intermitotic cell death, abnormal nuclear morphology and necrosis. This investigation explores the onset of apoptosis and abnormal morphology in response to 3 drugs i.e. Cisplatin, a novel Ferrocene (fctfa) ...

Prostate cancer is associated with the inability of prostatic epithelial cells to undergo apoptosis rather than with increased cell proliferation. Prostate apoptosis response-4 (Par-4) is a unique pro-apoptotic molecule that is capable of selectively inducing apoptosis in cancer cells when over-expressed, sensitizing the cells to diverse apoptotic stimuli and causing ...

Inhibition of proteasome activity is associated with a reduction in proliferation and apoptosis in cancer cells, depending upon the extent of inhibition. We have reported that a minimal inhibition of proteasome activity prevented adenosine 3'5'-cyclic monophosphate (cAMP)-induced differentiation and caused apoptosis in murine neuroblastoma (NB) cells in culture. In order ...

The objective of this study was to elucidate the role of the cellular proteasome on endotoxin-mediated activation of the macrophage. To study this role, THP-1 cells were stimulated with lipopolysaccharide (LPS) with selective cells being pretreated with the proteasome inhibitor, lactacystin or MG-132. LPS stimulation led to the phosphorylation and ...

The present work describes the development and optimization of a cell-based androgen reporter assay using the Chinese hamster ovarian cell line (CHO K1) in the 96-well format. The recent reports on increasing exposure of humans and wild-life to environmental endocrine disrupting chemicals (ED) prompt the need for high throughput screening ...

Proteasome inhibitor PS-341 induces growth arrest and apoptosis of multiple myeloma (MM) cells via inactivation of NF-kappaB in vitro and has afforded some objective responses in individuals with relapsed, refractory MM. However, the activity of PS-341 against non-hematological malignancies remains to be fully elucidated. In this study, we found that ...

The ubiquitin-proteasome pathway constitutes the major system for nuclear and extralysosomal cytosolic protein degradation in eukaryotic cells. A plethora of cell proteins implicated in the maintenance and regulation of essential cellular processes undergoes processing and functional modification by proteolytic degradation via the ubiquitin-proteasome pathway. Deregulations of the pathway have been ...

1-Methyl-4-phenylpyridinium (MPP(+)) is a neurotoxin that causes Parkinson's disease in experimental animals and humans. Despite the fact that intracellular iron was shown to be crucial for MPP(+)-induced apoptotic cell death, the molecular mechanisms for the iron requirement remain unclear. We investigated the role of transferrin receptor (TfR) and iron in ...

Two projects are described within the scope of this thesis. The first project characterizes the ubiquitin-specific protease UBP41 as a protein which upon overexpression causes apoptosis induction in several mammalian cancer cell lines. The second project investigates a possible involvement of the lysosomal cysteine proteases cathepsin-L and cathepsin-B in apoptosis ...

p16(INK4a) (hereafter referred to as p16), a major cyclin-dependent kinase (CDK) inhibitor, is the product of a tumor-suppressor gene that has been found inactivated in different cancer types. In the present study, we sought to investigate the role of p16 in apoptosis induced by ultraviolet light (the most important etiological ...

Ubiquitin (Ub)-protein conjugation represents a novel means of posttranscriptional modification in a proteolysis-dependent or -independent manner. E3 Ub ligases play a key role in governing the cascade of Ub transfer reactions by recognizing and catalyzing Ub conjugation to specific protein substrates. The E3s, which can be generally classified into HECT-type ...

Curcumin is a natural polyphenolic compound having an antiproliferative property, which recent evidence suggests is due to its ability to induce apoptosis. However, the molecular mechanisms through which curcumin induces apoptosis are not fully understood. Here, we report that the curcumin-induced apoptosis is mediated through the impairment of the ubiquitin-proteasome ...

Activin, a member of the TGFbeta superfamily, is expressed in the prostate and inhibits growth. We demonstrate that the effects of activin and androgen on regulation of prostate cancer cell growth are mutually antagonistic. In the absence of androgen, activin induced apoptosis in the androgen-dependent human prostate cancer cell line ...

Clusterin gene expression is potently induced in experimental models in which apoptosis is activated, such as rat prostate involution following castration. Nevertheless, its precise physiological role has not yet been established, and both anti-apoptotic and pro-apoptotic functions have been suggested for this gene. Clusterin expression level depends on cell proliferation ...

12-O-tetradecanoylphorbolacetate (TPA) influences proliferation, differentiation, and apoptosis in a variety of cells including prostate cancer cells. Here, we show that androgen treatment potentiates TPA-induced apoptosis in androgen-sensitive prostate cancer LNCaP cells but not in androgen-independent prostate cancer cell lines DU145 and PC-3. The use of the antiandrogen bicalutamide (Casodex) rescued ...

The ubiquitin-proteasome pathway (UPP) is a predominantly non-lysosomal protein degradation pathway responsible for degrading many critical regulatory proteins (e.g., nuclear factor-kappa B). This pathway is widely known for its ubiquitous role in immune and inflammatory responses, control of cell growth and apoptosis. These roles are apparent in the nervous system, ...

The immunosuppressive agent cyclosporin A (CsA), which interferes with signal transduction pathways leading to cytokine gene transcription in activated T cells, was investigated regarding its ability to induce apoptosis in T cells undergoing cell cycle progression and activation. In Jurkat and peripheral CD4+ T cells, CsA was found to markedly ...

The phosphatidylinositol 3-kinase (PI3K)/Akt pathway controls several important biological functions, such as cell growth regulation, apoptosis, and migration. However, the way in which PI3K/Akt controls androgen receptor (AR)-mediated prostate cancer cell growth remains unclear and controversial. Here, we demonstrate that the PI3K/Akt pathway regulates AR activity in a cell passage ...

Growth factor deprivation-induced apoptosis has been shown in various cell systems and is recognized as one of the standard models for the study of programmed cell death. The mechanism of induction of apoptosis by serum deprivation is still not clear. The objective of the present study was to investigate if ...

The proteasome plays a key role in regulating protein degradation in eukaryotic cells. A range of synthetic inhibitors of proteasome activity have been developed which have helped elucidate its role in the cell. These inhibitors have selectively induced apoptosis in malignant cells in vitro suggesting that the proteasome may be ...

Genistein, a naturally occurring isoflavone found chiefly in soybeans, has been reported to be a potent antitumor agent. Genistein is presumed to exert multiple effects related to the inhibition of cancer growth. Metastatic melanoma is a chemotherapy-refractory neoplasm. The present study was designed to explore the possible activity of genistein ...

We have previously reported the selection of a radioresistant human neuroblastoma cell line, Clone F, from IMR32 cells. We have shown that clonogenic radioresistance in these cells is accompanied by a reduced level of radiation-induced apoptosis [Cancer Res 55 (1995) 4915]. Here, we measured the response of these lines to ...

In the last few years, the ubiquitin(Ub)/proteasome system has become increasingly recognized as a controller of numerous physiological processes, including signal transduction, DNA repair, chromosome maintenance, transcriptional activation, cell cycle progression, cell survival, and certain immune cell functions. This is in addition to its more established roles in the removal ...

Proteasome inhibitors are potent inducers of cell death. The cytotoxic effect of proteasome inhibitors in general appears to be selective for proliferating cells, while quiescent cells seem to be protected. Conflicting results have been reported on the role of the CKI p27Kip1 either in promoting or inhibiting apoptosis mediated by ...

There is a considerable database on the effector mechanisms for CD8 recognition of PDC-E2 in primary biliary cirrhosis (PBC). In particular, the specific roles of MHC class I, the mitochondrial autoepitope, and the liver-specific T cell precursor frequency, are defined for HLA-A2.1 patients. There is evidence for a role of ...

Reactive oxygen species (ROS) have been suggested as important mediators of cisplatin-induced acute renal failure in vivo. However, our previous studies have shown that cisplatin-induced cell death in vitro could not be prevented by scavengers of hydrogen peroxide and hydroxyl radical in rabbit renal cortical slices. This discrepancy may be ...

We have previously shown that the clinically relevant polyamine analog N1,N11-diethylnorspermine (DENSPM) causes rapid apoptosis in human melanoma SK-MEL-28 cells via a series of events that include mitochondrial release of cytochrome c and activation of the caspase cascade. Upstream to these events, DENSPM downregulates polyamine biosynthesis and potently upregulates polyamine ...

Shiga toxin (Stx) has been implicated in the pathogenesis of several human and animal disease states. A key host target of Stx is the endothelial cell. Stx induces endothelial cell apoptosis through a mechanism that remains unknown. In the present report, we demonstrate that Stx-1 and Stx-2 inhibit endothelial cell ...