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PubMed2005

The inflammatory versus constitutive trafficking of mononuclear phagocytes into the alveolar space of mice is associated with drastic changes in their gene expression profiles.

Mononuclear phagocytes enter the lungs both constitutively to maintain alveolar macrophage and dendritic cell homeostasis, as well as during lung inflammation, where the role of these cells is less well defined. We used a transgenic mouse strain (CX3CR1(+/GFP)) that harbors a GFP label in circulating monocytes to identify and sort these cells from the vascular and alveolar compartments under both constitutive and acute lung inflammatory conditions. Using nylon arrays combined with real-time RT-PCR for gene expression profiling, we found that flow-sorted, highly purified mononuclear phagocytes recruited to acutely inflamed mouse lungs showed strongly up-regulated mRNA levels of the neutrophil chemoattractants KC, MIP-2, and IP-10, which contrasted with alveolar mononuclear phagocytes that immigrated in steady state. Similar observations were made for the lysosomal cathepsins B, L, and K being strongly up-regulated in mononuclear phagocytes upon recruitment to inflamed lungs but not during constitutive alveolar immigration. Inflammatory elicited mononuclear phagocytes also demonstrated significantly increased mRNA levels of the cytokine TNF-alpha and the PRR-associated molecules CD14, TLR4, and syndecan-4. Together, inflammatory elicited mononuclear phagocytes exhibit strongly increased neutrophil chemoattractants, lysosomal proteases, and LPS signaling mRNA transcripts, suggesting that these cells may play a major role in acute lung inflammatory processes.

Acute Disease↗

PubMed2005

Defined blocks in terminal plasma cell differentiation of common variable immunodeficiency patients.

Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by defective Ab production and recurrent bacterial infections. The largely unknown causes are likely to comprise a diverse set of genetic or acquired defects. In this study, we investigated terminal B cell differentiation in lymph nodes from CVID patients. Up to the germinal center B cell stage, B cell differentiation was normal but terminal plasma cell development was found to be impaired. Using differential Blimp-1 and Syndecan-1 expression in controls, we defined three different plasma cell subsets that correspond to progressive developmental stages locating to different sites in the lymph node. In the CVID patients, we could only detect one or two of these subsets indicating a defective differentiation. Thus, terminal plasma cell differentiation was found to be impaired despite normal expression of Blimp-1. B cells reaching only the first stage of plasma cell differentiation were further unable to undergo isotype switching and to up-regulate activation markers on B cells stimulated in vitro.

Adult↗

PubMed2006

The glycosaminoglycan-binding domain of decoy receptor 3 is essential for induction of monocyte adhesion.

Decoy receptor 3 (DcR3), a soluble receptor for Fas ligand, LIGHT (homologous to lymphotoxins shows inducible expression and competes with HSV glycoprotein D for herpes virus entry mediator, a receptor expressed by T lymphocytes), and TNF-like molecule 1A, is highly expressed in cancer cells and in tissues affected by autoimmune disease. DcR3.Fc has been shown to stimulate cell adhesion and to modulate cell activation and differentiation by triggering multiple signaling cascades that are independent of its three known ligands. In this study we found that DcR3.Fc-induced cell adhesion was inhibited by heparin and heparan sulfate, and that DcR3.Fc was unable to bind Chinese hamster ovary K1 mutants defective in glycosaminoglycan (GAG) synthesis. Furthermore, the negatively charged, sulfated GAGs of cell surface proteoglycans, but not their core proteins, were identified as the binding sites for DcR3.Fc. A potential GAG-binding site was found in the C-terminal region of DcR3, and the mutation of three basic residues, i.e., K256, R258, and R259, to alanines abolished its ability to trigger cell adhesion. Moreover, a fusion protein comprising the GAG-binding region of DcR3 with an Fc fragment (DcR3_HBD.Fc) has the same effect as DcR3.Fc in activating protein kinase C and inducing cell adhesion. Compared with wild-type THP-1 cells, cell adhesion induced by DcR3.Fc was significantly reduced in both CD44v3 and syndecan-2 knockdown THP-1 cells. Therefore, we propose a model in which DcR3.Fc may bind to and cross-link proteoglycans to induce monocyte adhesion.

Animals↗

PubMed2003

[Metabolism of heparan sulfate proteoglycans in Drosophila cell lines].

Proteoglycans with glycosaminoglycan side chains are found on the cell surface and in the extracellular matrix. Recently, it has been demonstrated that they are widely distributed in invertebrates, as well as in vertebrates. In the fruit fly, Drosophila melanogaster, core proteins of heparan sulfate proteoglycans (HSPGs), including division abnormally delayed (dally), dally-like, perlecan, and syndecan, have been identified by genetic analyses. Biochemical studies of the glycosaminoglycan structure in Drosophila have also found the presence of chondroitin sulfate, in addition to heparin sulfate; however, its core protein remains to be identified. Functional studies of HSPG in Drosophila have shown that dally and dally-like (members of glypican) are required for Wingless (a member of the Wnt family) signaling, and they are also implicated in affecting signaling of Decapentaplegic (a member of the transforming growth factor-beta/bone morphogenetic protein superfamily). Further evidence that HSPGs play important roles in these cellular signaling processes has been established from studies of genetic mutants defective in biosynthetic enzymes of HSPGs, such as sugarless (a homologue of UDP dehydrogenase), sulfateless (a homologue of HS N-deacetylase/N-sulfotransferase), and tout-velu (a homologue of Ext encoding HS polymerase). In this paper, the metabolism of Drosophila HSPGs was investigated to further clarify their biological functions, in two Drosophila cell lines: S 2 cell and Kc cell, using metabolic labeling techniques in combination with various pulse-chase protocols.

Animals↗

PubMed2004

[cDNA macroarray analysis of genes responsible for cartilage formation].

The aim of this study was to identify genes responsible for the formation and maintenance of cartilage tissue. For this purpose, gene expression patterns were compared between differentiating and dedifferentiating chondrocytes by cDNA macroarray analysis. A total of 1,186 genes were examined, and at least 7 genes were identified as candidate genes having critical roles in cartilages. Three of them encode well-known cartilage matrix molecules: aggrecan, decorin and type IX collagen, and others were preproenkephalin A, Early Growth Response-1, Early Growth Response-3, and basigin. All these genes were expressed at high level in mature cartilage, but their expressions were suppressed in response to dedifferentiation of chondrocytes. Meanwhile, transcription factor ALY, variant in the kinase (vik), and syndecan 2 genes were newly activated during the process of chondrocyte dedifferentiation. A similar process is somewhat observed in osteoarthritis. Therefore, activation of these genes might be closely related to the progression of osteoarthritis and would be a useful marker for it.

Aggrecans↗

PubMed1999

B cell response after MMTV infection: extrafollicular plasmablasts represent the main infected population and can transmit viral infection.

The immune response to mouse mammary tumor virus (MMTV) relies on the presentation of an MMTV-encoded superantigen by infected B cells to superantigen-specific T cells. The initial extrafollicular B cell differentiation involved the generation of B cells expressing low levels of B220. These B220low B cells corresponded to plasmablasts that expressed high levels of CD43 and syndecan-1 and were CD62 ligand- and IgD-. Viral DNA was detected nearly exclusively in these B220low B cells by PCR, and retroviral type-A particles were observed in their cytoplasm by electron microscopy. An MMTV transmission to the offspring was also achieved after transfer of B220low CD62 ligand- CD43+ plasmablasts into noninfected females. These data suggest that B220low plasmablasts, representing the bulk of infected B cells, are capable of sustaining viral replication and may be involved in the transmission of MMTV.

Animals↗

PubMed1998

[The role of beta1 integrins in renal failure accompanied by multiple myeloma].

Clinical features of multiple myeloma are linked with immunological phenotype of myeloma cells. The interactions between malignant plasma cells and proteins of ECM (extracellular matrix) or different cells results from the influence of adhesion molecules. In our study the expression of CD49b, CD49d, CD49e, CD49f on the myeloma cells has been estimated. These cells were obtained from bone marrow of 33 just diagnosed patients. Immunophenotyping was performed with flow cytometry method. Malignant plasma cells were identified by monoclonal antibody anti-CD138 (B-B4) directed against Syndecan-1. We have observed that in patients with high expression of laminin receptors CD49b, CD49f and lack of fibronectin receptors CD49d, CD49e more often renal failure has been confirmed.

Acute Kidney Injury↗

PubMed1999

Molecular IgV(H) analysis demonstrates highly somatic mutated B cells in synovialitis of osteoarthritis: a degenerative disease is associated with a specific, not locally generated immune response.

In osteoarthritis (OA), the synovial tissue exhibits a nonfollicular inflammatory infiltration with a characteristic arrangement of lymphocytes and plasma cells. These arrangements are either small perivascular aggregates with plasma cells surrounding the lymphocytes or small groups of plasma cells, located in the vicinity of small blood vessels. These patterns suggest that B lymphocytes directly differentiate into plasma cells. To understand the B-cell response in OA, we analyzed the V(H) genes from B cells of synovial tissue of nine OA patients (average age, 71.5+/-10.5 years; six female and three male). V(H) gene repertoires were determined from RNA prepared from tissue cryosections and from DNA of single isolated B lymphocytes and plasma cells. The inflammatory infiltrate was analyzed immunohistochemically by detecting CD20, Ki-M4 (follicular dendritic cells), CD4, IgG, IgM, IgA, Ki-67, and by simultaneous demonstration of the plasma-cell-specific antigen CD138 (syndecan-1) and factor VIII. The molecular data demonstrate B cells with a high number of somatic mutations (average, 16.5 to 19.8), and high ratios of replacement to silent mutations in the small lymphocytic/plasmacellular aggregates of OA. In the tissue cryosections, the values of the sigmaR/sigmaS at the complementarity determining regions were 5.3 and 2.0 in the framework regions. For both the isolated B lymphocytes and plasma cells, the value of this ratio in the complementarity determining regions was 3.5. In the framework regions, the values of this ratio were 2.0 for the isolated B cells and 1.8 for the plasma cells. B lymphocytes and plasma cells exhibited a distribution not described thus far. Two patterns of B-cell distribution could be observed: (a) Centrally located CD20+ B and CD4+ and CD8+ T lymphocytes were surrounded directly by IgG (predominantly) or IgA and IgM plasma cells. No proliferating Ki-67-positive cells and no follicular dendritic cells (germinal centers) could be detected in the aggregates; (b) Plasma cells (predominantly IgG) were located directly near endothelial cells of small blood vessels. The finding of highly mutated V(H) genes in B lymphocytes and the characteristic arrangement of B lymphocytes and plasma cells suggests that B cells, which participate in OA synovialitis, have undergone germinal center reaction at different sites. This may explain the low inflammatory infiltration without germinal centers in OA, which is a feature of this primarily degenerative joint disease.

Aged↗

PubMed2000

The alpha-defensins stimulate proteoglycan-dependent catabolism of low-density lipoprotein by vascular cells: a new class of inflammatory apolipoprotein and a possible contributor to atherogenesis.

Inflammation may contribute to the pathogenesis of atherosclerosis. On the basis of previous reports that human atherosclerotic lesions contain alpha-defensins, a class of cationic proteins released by activated neutrophils, the study was designed to ask whether defensins modulate the binding and catabolism of low-density lipoprotein (LDL) by human vascular cells. The results of the study demonstrated that defensin stimulated the binding of (125)I-LDL to cultured human umbilical vein endothelial cells, smooth muscle cells, and fibroblasts approximately 5-fold in a dose-dependent and saturable manner. Defensin and LDL formed stable complexes in solution and on cell surfaces. Stimulation of LDL binding by defensin was not inhibited by antibodies against the LDL-receptor (LDL-R), or by recombinant receptor-associated protein, which blocks binding of ligands to the alpha(2)-macroglobulin receptor/LDL-R-related protein and other LDL-R family members. Furthermore, defensin stimulated the binding, endocytosis, and degradation of LDL by fibroblasts lacking LDL-R. Stimulation of LDL degradation by defensin was inhibited approximately 75% by low concentrations of heparin (0.2 units/mL) and was similarly reduced in CHO cells lacking heparan-sulfate-containing proteoglycans. The effect of defensin was substantially increased in cells overexpressing the core protein of the syndecan-1 heparan sulfate proteoglycan. The alpha-defensins released from activated neutrophils may provide a link between inflammation and atherosclerosis by changing the pattern of LDL catabolism from LDL-R to the less efficient LDL-R-independent, proteoglycan-dependent pathway. (Blood. 2000;96:1393-1398)

Animals↗

PubMed2001

Identification of genes expressed in the Xenopus inner ear.

Recent studies indicate that hearing loss in humans has strong hereditary components associated with expression of specific genes in the auditory apparatus of the inner ear. However, the inner ear poses challenges for molecular research because the amount of tissue that can be isolated is limited, and extraction procedures yield small quantities of RNA and protein. To begin to identity genes essential for auditory function, we synthesized a cDNA library using an RT-PCR protocol and total RNA isolated from eight Xenopus laevis inner ears. Sequence analysis of randomly selected clones demonstrated expression of both identified (calmodulin, SNARE protein, syndecan-2) and unidentified genes, and confirmed synthesis of full length transcripts. Confocal and scanning electron microscopy (SEM) were used to examine the structure of inner ear organs that serve as auditory receptors in amphibians: the sacculus, the amphibian papilla and the basilar papilla. SEM images illustrate the heterogeneity of bundle morphology and demonstrate the continuous appearance of stereociliary bundles in the X. laevis amphibian papilla during larval development and adult life. Investigations of gene expression in Xenopus auditory organs using clones recovered from inner ear cDNA libraries should provide insight regarding the molecular basis of hearing.

Animals↗

PubMedDate not supplied

Synthesis and expression of mRNA encoding for different versican splice variants is related to the aggregation of human epithelial mesothelioma cells.

Malignant mesothelioma often has a biphasic growth pattern of epithelial and/or sarcomatous morphology. In culture, epithelial cells form aggregates, whereas fibroblast-like cells do not. Two human mesothelioma cell sub-lines, one with epithelial differentiation and the other with fibroblast-like phenotype were studied. We have previously shown (Dobra et al, 2000) that distinct types of the cell-associated syndecans are involved in the regulation of mesothelioma cell differentiation, whereas the role of matrix proteoglycans (PGs) remains unknown. This study was undertaken to examine whether cell aggregation of the epithelial mesothelioma cells correlates to the differential expression of the matrix PGs versican and perlecan at different degrees of confluence. PGs were isolated from the culture medium using ion-exchange chromatography and identified by high-performance liquid chromatography, capillary electrophoresis and Western blotting. Fibroblast-like cells express substantially more versican than epithelial cells. RT-PCR showed that both cell lines express mRNA coding for versican splice variants V0 and V1, but not for V2. The dominating splice variant in both cell lines is the V0. Screening of versican splice variants in various degrees of culture confluence showed that the expression of mRNA conding for the versican splice variants V0 and V1 is different only in confluent cultures. No significant differences in the expression of perlecan between the two cell lines were recorded. These results suggest that the aggregation of epithelial cells is related to a significant decrease (p < or = 0.001) of the splice variant V1. This variant seems to be a biologically active constituent that affects tumor biology.

Alternative Splicing↗

PubMed2003

Identification of signature genes by microarray for acute myeloid leukemia without maturation and acute promyelocytic leukemia with t(15;17)(q22;q12)(PML/RARalpha).

Acute myeloid leukemia (AML) has distinct subgroups characterized by different maturation and specific chromosomal translocation. In order to gain insight into the gene expression activities in AML, we carried out a gene expression profiling study with 21 AML samples using cDNA microarrays, focusing on acute promyelocytic leukemia with specific translocation t(15;17)(q22;q12) [French-American-British or FAB-M3 with t(15;17)] and AML without maturation (FAB-M1) characterized by morphologically and phenotypically immature AML blasts and no recurrent chromosomal abnormalities. Using a multivariate sigma-classifier algorithm, we identified 33 strong feature genes that distinguish FAB-M3 with t(15;17) from other AML samples, and 24 strong feature genes that classify FAB-M1. A direct comparison between FAB-M3 with t(15;17) and FAB-M1 led to selection of 13 strong feature genes. Those genes include some known to be related to leukemogenesis and cell differentiation. RIN1, a gene in the ras pathway, was up-regulated in FAB-M3 with t(15;17). Growth factor-binding protein 2 gene was down-regulated in FAB-M1. Huntingtin gene was up-regulated in FAB-M1. Others include syndecan 4, interleukin-2 receptor beta, folate receptor beta, low affinity immunoglobulin gamma, Fc receptor IIC precursor, insulin-like growth factor binding protein 2, and myeloperoxidase, which are involved in cell differentiation. Overexpression of myeloperoxidase in FAB-M3 cells with t(15;17) compared to FAB-M1 cells is consistent with the conventional cytochemical staining pattern. Thus, the study revealed that a morphologically-defined FAB-M1 subtype has a distinct gene expression signature that contributes to its cell differentiation and proliferation as well as FAB-M3 with a recurrent cytogenetic abnormality t(15;17)(q22;q12).

Algorithms↗

PubMed1992

Cell surface heparan sulfate proteoglycans from human vascular endothelial cells. Core protein characterization and antithrombin III binding properties.

Human aortic endothelial cells (HAEC) and human umbilical vein endothelial cells (HUVEC) were labeled with 35SO(4)2- for 48 h. The membrane-associated proteoglycans were solubilized from these monolayers with detergent and purified by ion-exchange chromatography on Mono Q, incorporation in liposomes, and gel filtration. The liposome-intercalated proteoglycans were 125I-iodinated and treated with heparitinase before SDS-polyacrylamide gel electrophoresis. Radio-labeled proteins with apparent molecular masses of 130, 60, 46, 35, and 30 kDa (HAEC) and 180, 130, 62, 43, and 35 kDa (HUVEC) were detected by autoradiography. Further characterization by affinity chromatography on immobilized monoclonal antibodies and by Northern blot analysis provided evidence for the expression of syndecan, glypican, and fibroglycan in human endothelial cells. Most of the heparan sulfate which accumulated in the subendothelial matrix was implanted on a 400-kDa core protein. This protein was immunologically related to perlecan and bound to fibronectin. Binding studies on immobilized antithrombin III suggested that all membrane-associated heparan sulfate proteoglycan forms had the capacity to bind to antithrombin III but that high affinity binding was more typical for glypican. Most of the proteoglycans isolated from the extracellular matrix also bound only with low affinity to antithrombin III. These results imply that glypican may specifically contribute to the antithrombotic properties of the vascular wall.

Antithrombin III↗

PubMed2003

Identification of genes expressed in a human scleral cDNA library.

PURPOSE: Clones established from a human scleral cDNA library were systematically sequenced. Public database sequence comparisons were performed to generate a profile of genes expressed in the human sclera and identify candidate genes for inherited diseases with scleral involvement. METHODS: A directionally cloned pCMV-PCR cDNA library was constructed from RNA isolated from scleras of human donor eyes with known plano refractive history. Plasmid DNA was extracted from randomly selected cDNA clones, and the insert sequences were determined by 5' end single-pass sequencing. Expressed sequence tags (ESTs) were generated and analyzed with the GenBank BLASTN program to identify sequence homologies to known genes. RESULTS: A total of 609 ESTs underwent BLAST analysis. Of these, 341 (56%) matched 228 known human genes and 4 non-human genes, 252 matched uncharacterized ESTs, and 16 showed no significant homology to human or non-human known sequences. The most redundant connective tissue-related genes were alphaA-crystalline, Xalpha-1 collagen, and beta-5 integrin. Other extracellular matrix gene matches were biglycan, syndecan, decorin, fibromodulin, proline arginine-rich end leucine-rich repeat protein, transgelin, TIMP-1, and fibulin 1. Human scleral expression of all but decorin and biglycan has not previously been reported. CONCLUSIONS: This effort provides the first partial list of genes expressed in human sclera. Identification of genes expressed in the sclera contributes to our understanding of scleral biology, and potentially provides positional candidate genes for scleral disorders such as high myopia.

Adult↗

PubMed2003

Role of Id-2 in the maintenance of a differentiated and noninvasive phenotype in breast cancer cells.

Id proteins are inhibitors of basic helix-loop-helix transcription factors and generally stimulate cell proliferation and inhibit differentiation. We have shown that ectopic expression of Id-1 in murine mammary epithelial cells resulted in loss of differentiation and gain of invasive and proliferative abilities. Moreover, Id-1 was highly expressed in aggressive breast cancer cells in culture and in biopsies from infiltrating carcinomas. In contrast to Id-1, we found that, in vitro and in vivo, Id-2 mRNA and protein were up-regulated as mammary epithelial cells lost proliferative capacity and initiated differentiation. We further determined that this up-regulation of Id-2 was a necessary step toward a fully differentiated phenotype in breast cells. Here we show that one of the components of the extracellular matrix network, laminin, is responsible for the increase in Id-2 expression during differentiation. We also show that Id-2 expression is inversely correlated with the rate of proliferation in murine mammary epithelial cells and that Id-2 is expressed at a higher level in differentiated human breast cancer cells in comparison with very aggressive and metastatic cells. When reintroduced in aggressive breast cancer cells, Id-2 is able to reduce their proliferative and invasive phenotypes and decrease their level of matrix metalloproteinase 9 secretion as well as increase syndecan-1 expression. Moreover, little Id-2 protein expression is detectable in human biopsies from aggressive and invasive carcinomas in comparison with in situ carcinomas. In conclusion, Id-2 expression not only follows a pattern opposite to that of Id-1 during mammary gland development and breast cancer progression but also appears to act as an important protein for the maintenance of a differentiated and noninvasive phenotype in normal and transformed breast cells.

Animals↗

PubMed1992

The role of growth factors in determination and differentiation of the odontoblastic cell lineage.

In developing teeth the differentiation of odontoblasts is triggered by the enamel epithelium and is tightly coupled with morphogenesis. There is substantial evidence that even in mature teeth the cells of the dental pulp retain the capability to differentiate into odontoblasts under suitable conditions. However, cells from other than the dental mesenchymal cell lineage apparently do not possess this potential. Thus, it is conceivable that the dental mesenchymal cells acquire cell type-specific potential to differentiate into odontoblasts during their developmental history. Therefore, the understanding of the mechanisms which regulate the terminal differentiation of odontoblasts requires that the molecular changes and mechanisms that are associated with their progressive determination be clarified. It can be speculated that there are key transition points in the developmental sequence during which the mesenchymal cells acquire new levels of differentiation. These include, (1) the condensation of the neural crest-derived mesenchymal cells around the epithelial bud, (2) their entrance into the dental papilla lineage during cap stage, and (3) the differentiation of the cells underlying the enamel epithelium into odontoblasts during bell stage. The transition points are conceivably characterized by amplification or onset of expression of new sets of genes encoding transcription factors, growth factors as well as structural proteins. We have applied in situ hybridization for localization of the expression of two growth factors during mouse molar morphogenesis: transforming growth factor beta 1 (TGF beta 1) and int-2 (a proto-oncogene coding for a fibroblast growth factor-related protein). During bud stage, expression of TGF beta 1 was first detected in the epithelium and shortly thereafter in the condensed dental mesenchyme. The expression was weak during early bell stage but a high number of transcripts appeared in secretory odontoblasts as well as in presecretory ameloblasts. int-2 mRNA appeared in the dental papilla mesenchyme at the onset of cap stage, persisted in the cuspal mesenchyme during bell stage and was lost upon completion of morphogenesis. Our findings suggest that cell type-specific expression of TGF beta 1 and int-2 is associated with phenotypic properties of the odontoblastic cell lineage. For instance, TGF beta 1 may regulate matrix deposition by increasing tenascin and syndecan expression in the condensed dental mesenchyme and by controlling dentin matrix deposition by odontoblasts. TGF beta 1 and int-2 may also be involved in signalling between the epithelial and mesenchymal tissues and in regulation of gene expression at the transition points of the developmental sequence that leads to the differentiation of odontoblasts.

Animals↗

PubMed2004

Mitogenic signal transduction by integrin- and growth factor receptor-mediated pathways.

Engagement of cells with the extracellular matrix (ECM) proteins is crucial for various biological processes, including cell adhesion, spreading, proliferation, differentiation, migration, apoptosis, and gene induction, contributing to maintenance of tissue integrity, embryogenesis, wound healing, and the metastasis of tumor cells (Hynes, 2002b; Juliano, 2002). The engagement involves cell adhesion mediated by integrins, a large family of cell adhesion receptors that are transmembrane glycoproteins which bind to ECM or to counter-receptors on neighbor cells. In this review, the molecular basis of signaling mediated by integrins and their collaboration with growth factor receptors will be discussed, based on recent observations. Although other cell adhesion receptors including cadherins, selectins, syndecans, and the immunoglobulin superfamily of cell adhesion molecules (IgCAMs) can play important roles or be involved in these processes, we suggest readers refer to recent outstanding reviews on them (Barclay, 2003; Brummendorf and Lemmon 2001; Panicker et al. 2003).

Actins↗

PubMedDate not supplied

Mevastatin-induced apoptosis and growth suppression in U266 myeloma cells.

Statins have been used successfully in the treatment of hypercholesterinaemia. Moreover, in vitro studies have shown that statins can trigger apoptosis in a variety of tumor cell lines. In the present study we analysed the effect of mevastatin--a novel inhibitor of HMG-COA reductase, the rate-limiting enzyme of the mevalonate pathway--on U266 human myeloma cells. Apoptosis induced by mevastatin was associated with increased caspase activity and depolarisation of the mitochondrial membrane. Expression of Bcl-2 mRNA and protein was down-regulated, with no change in Bax or Bcl-XL protein production. The mitochondrial program was supported by caspase-8 and cleaved-Bid activity. None of the antibodies neutralizing the death-ligand/death-receptor pathway--TRAIL-R2Fc, anti-TNF-alpha, anti-FASL(NOK-1)--influenced the mevastatin-induced apoptosis. Mevastatin also stimulated shedding of syndecan-1 from the surface of myeloma cells. The apoptosis inducing effect of mevastatin could be considered as a potential participant in a complex antitumor protocol.

Apoptosis↗