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PubMed1999

Adhesion to fibronectin promotes the activation of the p125(FAK)/Zap-70complex in human T cells.

The beta1 integrins are a family of heterodimeric adhesion receptors involved in cell-to-cell contacts and cell-to-extracellular matrix interactions. Through their adhesive role, integrins participate in transduction of outside/inside signals and contribute to trigger a multitude of cellular events such as differentiation, cell activation, and motility. The fibronectin integrin receptors, alpha4beta1 and alpha5beta1, can function as costimulatory molecules in T-cell receptor (TCR)-dependent T-cell activation. In the current study the Jurkat T-cell line was used as a model system to investigate the TCR-independent role of cell adhesion to fibronectin in the activation of Zap-70, a central molecule in the signalling events in T cells. Upon adhesion to plastic immobilized fibronectin but not to bovine serum albumin (BSA) the phosphorylation of p125FAK, a protein kinase that localizes to focal adhesion sites, was induced. Moreover, clustering of fibronectin receptors led to the detection of a p125FAK/Zap-70 complex. Finally, while the complex between fak-B, another protein kinase localized to focal adhesion sites, and Zap-70 was detected in cells plated either on BSA or on fibronectin, the formation of the p125FAK/Zap-70 complex appeared specifically induced following fibronectin-mediated integrin clustering. These data suggest the existence of a high degree of specificity when the members of the beta1 integrin family mediate signalling pathways in T cells.

Cell Adhesion↗

PubMed2002

Regulatory effects of stem cell factor and interleukin-4 on adhesion of human mast cells to extracellular matrix proteins.

Mast cells are inflammatory and immunoregulatory cells resident in tissues. They develop from bone marrow-derived progenitor cells that enter the tissue through the blood circulation. The specific localization and migration of mast cells in tissues is dependent on their interaction with extracellular matrix (ECM) proteins. Adhesion of human mast cells isolated from intestinal mucosa and cultured in the presence of stem cell factor (SCF) to ECM proteins is analyzed. It was observed that SCF is a unique cytokine enhancing mast cell adhesion to all tested ECM proteins (fibronectin, laminin, collagen I, III, IV, VI, XIV) up to 5-fold, particularly to fibronectin (54% +/- 12% of mast cells) and to denatured collagens (40% +/- 12% on cyanogen bromide-cleaved peptides of collagen I). Most noteworthy, preculture of mast cells with interleukin-4 (IL-4), in addition to SCF, reduced their potency to adhere to ECM proteins to one third compared to mast cells cultured with SCF alone. Mast cell adhesion was preferentially mediated by beta1 integrins, and most cells expressed the ECM-binding integrins alpha2beta1, alpha3beta1, alpha4beta1, alpha5beta1, and alphaVbeta3. SCF-induced mast cell adhesion was totally blocked by wortmannin and apigenin, indicating an involvement of phosphatidylinositol 3-kinase and mitogen-activated protein kinase, and it was related to an up-regulation of the HUTS-21 beta1 epitope, which is associated with an activated conformation of beta1. In conclusion, these data indicate that SCF induces the adhesion of cultured mast cells to ECM proteins, whereas IL-4 may promote detachment from the ECM.

Cell Adhesion↗

PubMed2002

Characterization of organotypic keratinocyte cultures on de-epithelialized bovine tongue mucosa.

Organotypic cultures have been used to study epithelial cell behavior for many years. The aim of this study was to develop an organotypic culture method that better mimics the three-dimensional morphology of interdigitating rete ridges and connective tissue papillae and that also conserves the basement membrane zone (BMZ). Bovine tongue mucosa connective tissue, separated from epithelium after 1 M NaCl incubation, was used as organotypic culture substratum for different human keratinocyte cell lines. Organotypic cultures were characterized by electron and immunofluorescence microscopy for expression of integrin subunits and extracellular matrix components. While spontaneously immortalized mucosal keratinocytes produced highly irregular stratified organotypic cultures, the normal human epidermal keratinocytes (NHEK) demonstrated culture morphology that resembled in vivo epidermis. However, in this model, the histomorphology, expression of differentiation markers involucrin, keratin 10 and 14, and integrins varied significantly between the cell lines. Some cultures appeared to have an extended survival since they were maintained up to 40 days without histological signs of degeneration. The ultrastructure of the BMZ including hemidesmosomes was similar to the normal dermo-epidermal junction. Extracellular matrix molecules, including tenascin, laminin-1 and -5, were expressed in the cultures demonstrating their secretion solely by keratinocytes. Distribution and expression of integrins in NHEK cultures was similar to that seen in vivo skin with the exception of additional expression of alpha5beta1 and alpha(v)beta6 integrins. Organotypic NHEK cultures show similarities to normal stratified epithelium and are potentially useful for multiple applications for studies on epithelial cell behavior in vitro.

Animals↗

PubMed1996

The anti-platelet and anti-thrombotic effects of FK633, a peptide-mimetic GPIIB/IIIA antagonist.

The anti-platelet and anti-thrombotic properties of FK633, a peptide mimetic GPIIb/IIIa antagonist were studied. In human platelet rich plasma, FK633 inhibited ADP-, collagen-, thrombin-, and PAF-induced platelet aggregation with IC50 values of 103, 87, 98, and 239 nM, respectively. RGDS acted similarly, but it's potency was about 1,000 times weaker than FK633, FK633 inhibited 125I-fibrinogen binding to human washed platelet with an IC50 of 88 nM. FK633 did not inhibit alphavbeta3, alpha5beta1, and alphavbeta1 integrin-mediated cellular adhesion up to 1.0mM, while RGDS inhibited all these interactions. In dogs, bolus injection of FK633 at 0.1 mg/kg significantly suppressed ex vivo ADP-induced platelet aggregation (>40% inhibition) and thrombus formation at stenosed and injured coronary artery, but did not prolong template bleeding time. However, FK633 inhibited >90% ADP-induced aggregation at 0.32 mg/kg, causing significant prolongation of the bleeding time. Thus, FK633 is a specific GPIIb/IIIa antagonist with potent anti-thrombotic effect in vivo, but careful dosing study might be necessary to avoid the bleeding complications in the clinic.

Animals↗

PubMed2003

Regulation, cellular localization, and function of the p75 neurotrophin receptor (p75NTR) during the regeneration of facial motoneurons.

The common neurotrophin receptor (p75NTR) is a member of the tumor necrosis factor receptor superfamily and binds the neurotrophins nerve growth factor, brain derived neurotrophic factor, neurotrophin-3, and neurotrophin-4. P75NTR is expressed on developing motoneurons and is reexpressed on adult motoneurons under pathological conditions such as nerve trauma or neurodegeneration. Here we examined the regulation and function of p75NTR during regeneration after peripheral transection of the facial nerve of adult mice. Axotomy led to a strong increase in p75NTR immunoreactivity on the injured and regenerating facial motoneurons and on denervated Schwann cells. Cellular colocalization also revealed p75NTR immunoreactivity on neighboring blood vessels and cells in the injured nerve, but not on activated GFAP+ astrocytes or alphaMbeta2+ microglia and macrophages. To determine the function of this receptor we examined the effects of p75NTR deficiency on neuroglial activation, on the speed of axonal regeneration, and on neuronal survival after facial axotomy in two different transgenic mouse lines carrying targeted insertions exon 4 (p75e4-/-) or exon 3 (p75e3-/-) of the p75NTR gene. In both animal models absence of p75NTR led to a twofold, early increase in the number of CD3+. T-cells and in the microglial immunoreactivity for the alpha5beta1, alpha6beta1, and alphaMbeta2 integrins at day 4 in the facial nucleus and in the crushed facial motor nerve. No changes were observed in the number of reactive GFAP+ astrocytes or on late microglial and lymphocyte responses. The rate of axonal elongation in the crushed facial nerve, as well as neuronal survival, was found to be unaffected. Overall, the current study shows that the p75NTR receptor plays an important regulatory role in early neuroglial and immune activation.

Animals↗

PubMed1998

Growth factors in infant germinal matrix: relationship to extracellular matrix and cell adhesion molecules.

We examined the expression of selected growth factors, growth factor receptors, elements of extracellular matrix and cell adhesion molecules in the germinal matrix layer (GML) utilizing immunohistochemistry and reverse transcriptase polymerase chain reaction. At autopsy brain samples from 10 neonatal infants were used. Epidermal growth factor receptor (EGFR) was significantly expressed in the matrix cells. While transforming growth factor alpha and heparin-binding epidermal growth factor-like growth factor were found in the matrix cells or vascular wall as ligands, epidermal growth factor was not expressed. EGFR and its ligands are thought to be important factors for the maintenance of the matrix cells and cell-to-cell interactions. Insulin like growth factor I, its receptor Ibeta and tenascin were found in the stroma of the GML and periventricular region. Vascular endothelial growth factor and receptor Flk-1, laminin A and B2, fibronectin, collagen type IV and integrins such as beta3, alpha5beta1 and alphaVbeta3 were found mainly in or around the vascular wall indicating their important roles for vascularization. Transforming growth factor beta2 and its receptor II were expressed in the matrix cells and/or vascular wall suggesting a role in proliferation and/or regression of the vasculature. CD44 and Thy-1 were also expressed in the matrix cells.

Autopsy↗

PubMed2005

Contortrostatin, a snake venom disintegrin with anti-angiogenic and anti-tumor activity.

Disintegrins are soluble peptides found in snake venom. They bind to Arg-Gly-Asp (RGD)-responsive integrins with high affinity (nM range) and block integrin function. Contortrostatin (CN), the disintegrin from southern copperhead venom, is a homodimer with a molecular weight of 13,500. Each chain contains 65 amino acids with an Arg-Gly-Asp motif. CN has anti-invasive and anti-adhesive activity on tumor cells and endothelial cells in vitro, and binds to integrins alphavbeta3, alphavbeta5, and/or alpha5beta1. In vivo studies using the human metastatic breast cancer cell line MDA-MB-435, in an orthotopic xenograft model in nude mice, revealed that CN has potent anti-tumor and anti-angiogenic activity. Recent studies have employed an intravenous liposomal delivery procedure. Liposomal delivery of CN has also been shown to provide effective in vivo anti-tumor and anti-angiogenic activity in a human ovarian cancer animal model.

Angiogenesis Inhibitors↗

PubMed1999

Cellular entry of hantaviruses which cause hemorrhagic fever with renal syndrome is mediated by beta3 integrins.

Hantaviruses replicate primarily in the vascular endothelium and cause two human diseases, hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). In this report, we demonstrate that the cellular entry of HFRS-associated hantaviruses is facilitated by specific integrins expressed on platelets, endothelial cells, and macrophages. Infection of human umbilical vein endothelial cells and Vero E6 cells by the HFRS-causing hantaviruses Hantaan (HTN), Seoul (SEO), and Puumala (PUU) is inhibited by antibodies to alphavbeta3 integrins and by the integrin ligand vitronectin. The cellular entry of HTN, SEO, and PUU viruses, but not the nonpathogenic Prospect Hill (PH) hantavirus (i.e., a virus with no associated human disease), was also mediated by introducting recombinant alphaIIbbeta3 or alphavbeta3 integrins into beta3-integrin-deficient CHO cells. In addition, PH infectivity was not inhibited by alphavbeta3-specific sera or vitronectin but was blocked by alpha5beta1-specific sera and the integrin ligand fibronectin. RGD tripeptides, which are required for many integrin-ligand interactions, are absent from all hantavirus G1 and G2 surface glycoproteins, and GRGDSP peptides did not inhibit hantavirus infectivity. Further, a mouse-human hybrid beta3 integrin-specific Fab fragment, c7E3 (ReoPro), also inhibited the infectivity of HTN, SEO, and PUU as well as HPS-associated hantaviruses, Sin Nombre (SN) and New York-1 (NY-1). These findings indicate that pathogenic HPS- and HFRS-causing hantaviruses enter cells via beta3 integrins, which are present on the surfaces of platelets, endothelial cells, and macrophages. Since beta3 integrins regulate vascular permeability and platelet function, these findings also correlate beta3 integrin usage with common elements of hantavirus pathogenesis.

Abciximab↗

PubMed1996

The inhibitory anti-beta1 integrin monoclonal antibody 13 recognizes an epitope that is attenuated by ligand occupancy. Evidence for allosteric inhibition of integrin function.

Integrin-ligand binding causes conformational changes in the integrin, as evidenced by the increased expression of epitopes known as ligand-induced binding sites. Some monoclonal antibodies (mAbs) that recognize ligand-induced binding sites stimulate ligand binding, possibly by stabilizing the ligand-occupied conformation of the integrin. Here we have investigated the effect of ligand recognition by alpha5beta1 on the binding of a mAb that inhibits beta1 integrin function (mAb 13). Ligand (fibronectin fragment or GRGDS peptide) decreased the binding of mAb 13 to alpha5beta1. Analysis of this inhibition showed that at high ligand concentrations, approximately 50% of the total integrin bound mAb 13 with >50-fold lower affinity than in the absence of ligand. The concentration of ligand required for half-maximal inhibition of antibody binding was independent of antibody concentration, suggesting that ligand acts as an allosteric inhibitor of mAb 13 binding. Hence, ligand and mAb 13 did not appear to compete directly for binding to alpha5beta1. The stimulatory anti-beta1 mAb 9EG7 was found to increase the maximum level of ligand binding approximately 2-fold, indicating that up to 50% of the total integrin could not bind ligand without 9EG7 stimulation. Analysis of mAb 13 binding in the presence of 9EG7 and ligand (i.e. maximal ligand occupancy) demonstrated that essentially all of the integrin bound mAb 13 with very low or zero affinity. Our results demonstrate that mAb 13 recognizes an epitope that is dramatically attenuated in the ligand-occupied form of alpha5beta1. Hence, since mAb 13 preferentially recognizes the unoccupied conformation of the integrin, the antibody may inhibit ligand binding by stabilizing the unoccupied state of alpha5beta1. In addition, we present evidence that the binding of mAb 13 to ligand-occupied alpha5beta1 may also induce a conformational change in the integrin, resulting in the displacement of ligand.

Allosteric Regulation↗

PubMed2001

A comparison of ocular melanocyte and uveal melanoma cell invasion and the implication of alpha1beta1, alpha4beta1 and alpha6beta1 integrins.

BACKGROUND/AIMS: Posterior uveal melanoma is the most common intraocular tumour in adults, responsible for the death of approximately 35% of patients. Hepatic metastases are most frequent, and once diagnosed survival is usually less than 1 year. The beta1 family of integrins, alphavbeta3 and MMP-2 and MMP-9 have been implicated in the metastasis of several types of tumour. To study their involvement in uveal melanoma we analysed the expression of the beta1 integrins, alphavbeta3, MMP-2, and MMP-9 in 10 primary posterior uveal melanomas, and correlated expression with invasive potential in vitro. Comparable studies were undertaken on cultures of melanocytes. METHODS: Expression of integrins was studied by immunohistochemistry, secretion of MMP-2 and MMP-9 by zymography, and the invasive potential was assessed using a transwell model. RESULTS: MMP-2 was secreted by all uveal melanomas and seven of 10 secreted MMP-9. Among uveal melanoma, invasion levels of 4-25% were observed and the major integrins expressed were alpha1beta1, alpha2beta1, alpha3beta1, alpha5beta1, and avbeta3. Melanocytes did not express alpha1beta1, alpha4beta1, and alpha6beta1. CONCLUSION: The laminin binding alpha6beta1 integrin was not expressed by either melanocytes or tumours with spindle morphology, which are considered to have a better prognosis. It is possible that expression of the alpha6beta1 integrin may prove useful as a prognostic indicator.

Adult↗

PubMed2005

Extracellular matrix-dependent regulation of angiogenin expression in human placenta.

Knowledge of the rapidly developing hierarchy of controls affecting vascular development in placenta is required to understand how the growth factors and their receptor-mediated signals actually produce vessels. At the cell biological level, these events clearly require stable interactions between the cells, and cells with the surrounding ECM. The objective of the study was to understand the role of integrins and ECM on the expression and secretion of angiogenin in placentas and from trophoblasts in culture. Functionally active term placental explant culture and trophoblast cultures were used to demonstrate the differential secretion profile of angiogenin and real-time quantitative RT-PCR to demonstrate the mRNA expression in the presence or absence of ECM proteins. In this study, a significant increase in expression and secretion of angiogenin occurred in the presence of vitronectin (VN) and fibronectin (FN). Using antibody-blocking experiments it was also demonstrated that the angiogenin secretion is mediated by placental integrins, alpha(V)beta3 and alpha5beta1. In addition, exposure to hypoxic conditions resulted in diminished angiogenin secretion in the presence of both ECMs suggesting that angiogenin expression in the presence of ECM is modulated by local O2 concentration. In conclusion, this study provides evidence for the regulatory role of ECM and integrins on the mRNA expression and secretion of angiogenin in human placenta. ECMs may have a pivotal role in enhancing secretion of this peptide necessary for placental angiogenesis and provides the impetus as additional targets for the control of angiogenesis in pathological pregnancy.

Cell Line, Tumor↗

PubMed1999

Integrin and neurocan binding to L1 involves distinct Ig domains.

The cell adhesion molecule L1, a 200-220-kDa type I membrane glycoprotein of the Ig superfamily, mediates many neuronal processes. Originally studied in the nervous system, L1 is expressed by hematopoietic and many epithelial cells, suggesting a more expanded role. L1 supports homophilic L1-L1 and integrin-mediated cell binding and can also bind with high affinity to the neural proteoglycan neurocan; however, the binding site is unknown. We have dissected the L1 molecule and investigated the cell binding ability of Ig domains 1 and 6. We report that RGD sites in domain 6 support alpha5beta1- or alphavbeta3-mediated integrin binding and that both RGD sites are essential. Cooperation of RGD sites with neighboring domains are necessary for alpha(5)beta(1). A T cell hybridoma and activated T cells could bind to L1 in the absence of RGDs. This binding was supported by Ig domain 1 and mediated by cell surface-exposed neurocan. Lymphoid and brain-derived neurocan were structurally similar. We also present evidence that a fusion protein of the Ig 1-like domain of L1 can bind to recombinant neurocan. Our results support the notion that L1 provides distinct cell binding sites that may serve in cell-cell or cell-matrix interactions.

Animals↗

PubMed2005

ADAM-Integrin Interactions: potential integrin regulated ectodomain shedding activity.

ADAMs (a disintegrin and metalloprotease) are a family of cell surface proteins related to the Class III snake venom metalloproteases (SVMP). ADAMs are members of the Metazincin family which includes the matrix matalloproteases and the ADAMTS proteins. Unlike their snake venom relatives, ADAMs are expressed as transmembrane cell surface proteins. The domain structure of ADAMs suggests that these proteins posses both proteolytic and adhesive functions. Several members of the ADAM protein family have been shown to be involved in ectodomain shedding of many important cell surface proteins resulting in the release of biologically active soluble factors. The carboxyl-terminal domains, especially the disintegrin-like domain of ADAMs, have been demonstrated to support cell adhesion. The disintegrin-like domains of many ADAMs are capable of acting as integrin ligands. Integrins known to interact with ADAM disintegrin-like domains include alpha4beta1, alpha4beta7, alpha5beta1, alpha6beta1, alpha9beta1, alphavbeta3, and alphavbeta5. This integrin mediated interaction of the disintegrin-like domains with the cell surface suggests that ADAMs may function as cellular counter receptors. In this review we discuss the individual functions ascribed to members of the ADAM family especially those related to integrin interactions and the potential for integrin mediated regulation of ectodomain shedding.

Animals↗

PubMed2006

Extracellular matrix regulates enhanced eotaxin expression in asthmatic airway smooth muscle cells.

RATIONALE: Altered airway smooth muscle (ASM) function and enrichment of the extracellular matrix (ECM) with fibronectin and collagen are key features of asthma. Previously, we have reported these ECM proteins enhance ASM synthetic function. OBJECTIVE: We compared ASM cultured from endobronchial biopsies from subjects with and without asthma to assess if asthmatic cells were hypersecretory and determined whether the underlying mechanism involved autocrine ECM production. METHODS AND MEASUREMENTS: Cells from subjects with and without asthma were cultured on plastic or in plates precoated with ECM proteins. Cytokine production was evaluated by enzyme-linked immunosorbent assay and by reverse transcriptase-polymerase chain reaction. Function-blocking integrin antibodies were used to identify integrin involvement. RESULTS: Baseline eotaxin and its production after stimulation with interleukin (IL)-13, IL-1beta, or tumor necrosis factor-alpha was increased (2.5- to 6.0-fold) in ASM cells cultured from subjects with asthma compared with healthy subjects. When seeded on ECM from asthmatic ASM, IL-13-dependent eotaxin release from healthy or asthmatic ASM was enhanced compared with culture on healthy ECM. The ECM substrates fibronectin and type I collagen each enhanced IL-13-dependent eotaxin release, and Western immunoblot indicated that fibronectin expression was higher in asthmatic ASM cells. Integrin-blocking antibodies revealed that alpha5beta1 was required for more than 50% of the enhanced IL-13-dependent eotaxin release by ASM cells from subjects with asthma, whereas alpha2beta1 or alphavbeta3 neutralization lacked effect. CONCLUSION: The data indicate that ASM cells cultured from subjects with asthma are hypersecretory compared with cells from healthy donors and that autocrine fibronectin secretion acting via alpha5beta1 in part underlies this effect.

Adult↗

PubMed1997

Roles of integrins in fibronectin matrix assembly.

Fibronectin (Fn) matrix assembly is a dynamic cellular process in which the soluble dimeric Fn molecules are assembled into insoluble, disulfide bond stabilized fibrillar polymeric matrix. Fn matrix assembly requires specific Fn binding integrins. Several Fn binding integrins that are capable of mediating Fn matrix assembly have been identified. They include alpha5beta1, alphaIIb(beta3) and alpha(v)beta3 integrins. Cells regulate the matrix assembly process not only by controlling cell surface expression level of the Fn binding integrins but also by modulating Fn binding and cytoskeleton binding activities of the integrins. A major challenge of future studies is to delineate the signal transduction pathway that regulates Fn matrix assembly.

Amino Acid Sequence↗

PubMed2000

The disintegrin-like domain of the snake venom metalloprotease alternagin inhibits alpha2beta1 integrin-mediated cell adhesion.

The alpha2beta1 integrin is a major collagen receptor that plays an essential role in the adhesion of normal and tumor cells to the extracellular matrix. Here we describe the isolation of a novel metalloproteinase/disintegrin, which is a potent inhibitor of the collagen binding to alpha2beta1 integrin. This 55-kDa protein (alternagin) and its disintegrin domain (alternagin-C) were isolated from Bothrops alternatus snake venom. Amino acid sequencing of alternagin-C revealed the disintegrin structure. Alternagin and alternagin-C inhibit collagen I-mediated adhesion of K562-alpha2beta1-transfected cells. The IC50 was 134 and 100 nM for alternagin and alternagin-C, respectively. Neither protein interfered with the adhesion of cells expressing alphaIIbeta3, alpha1beta1, alpha5beta1, alpha4beta1 alphavbeta3, and alpha9beta1 integrins to other ligands such as fibrinogen, fibronectin, and collagen IV. Alternagin and alternagin-C also mediated the adhesion of the K562-alpha2beta1-transfected cells. Our results show that the disintegrin-like domain of alternagin is responsible for its ability to inhibit collagen binding to alpha2beta1 integrin.

Amino Acid Sequence↗

PubMed2003

A targeted approach for antiangiogenic therapy of metastatic human colon cancer.

The realization that the growth and spread of tumors are dependent on angiogenesis has created new avenues of research designed to help us to better understand cancer biology and to facilitate the development of new therapeutic strategies. However, the process of angiogenesis consists of multiple sequential and interdependent steps with a myriad of positive and negative regulators of angiogenesis being involved. The survival of tumors and thus their metastases are dependent on the balance of endogenous angiogenic and antiangiogenic factors such that the outcome favors increased angiogenesis. Several growth factors have been identified that regulate angiogenesis in colon cancer; the most important of these is vascular endothelial growth factor. In addition, specific integrins such as alphavbeta3 and alpha5beta1 mediate endothelial cell survival and have been shown to be overexpressed on the endothelium of colon cancer. These angiogenic mediators thus serve as targets for therapy of metastatic colon cancer and have shown promise in preclinical trials.

Angiogenesis Inhibitors↗

PubMed2003

Curcumin exhibits antimetastatic properties by modulating integrin receptors, collagenase activity, and expression of Nm23 and E-cadherin.

Curcumin (diferuloyl methane), the major pigment from the rhizome of Curcuma longa L., has been widely studied for its tumor-inhibiting properties. Recent studies indicate that curcumin can modify cell receptor binding, it also affects intracellular signalling reactions. Curcumin-treated B16F10 melanoma cells formed eight-fold fewer lung metastases in C57BL6 mice. In the cell adhesion assays, curcumin-treated cells showed a dose-dependent reduction in their binding to four extracellular matrix (ECM) proteins. The binding to fibronectin, vitronectin, and collagen IV decreased by over 50% in 24 hours, and by 100% after 48 hours of curcumin treatment, it persisted at this level even after 15 days of cultivating cells in curcumin-free medium. Curcumin-treated cells showed a marked reduction in the expression of alpha5beta1 and alpha(v)beta3 integrin receptors. In addition, curcumin treatment inhibited pp125 focal adhesion kinase (FAK), tyrosine phosphorylation of a 120 kD protein, and collagenase activity. Curcumin enhances the expression of antimetastatic proteins, tissue inhibitor metalloproteinase (TIMP)-2, nonmetastatic gene 23 (Nm23), and E-cadherin. In this article we report on the effect of curcumin on the expression of integrin, TIMP-2, Nm23, E-cadherin, adhesion, and metalloproteinase activity.

Animals↗