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PubMedDate not supplied

Serum factors affecting the cell migration inhibition response to lepromin.

Cell migration inhibition of white blood cells in the presence of total protein lepromin (TPL) was studied in ten lepromatous patients, six tuberculoid patients, and ten normal controls; adding normal, tuberculoid, lepromatous, or no serum to the culture medium. Using normal or no serum, lepromatous patients and skin negative controls gave negative reactions, while tuberculoid patients and skin positive controls gave positive cell migration inhibitions. The addition of lepromatous serum gave a very significant overall increase of migration indices in all groups of subjects, turning to negative the positive reactions of lepromatous patients and positive controls. On the contrary, the addition of tuberculoid serum gave a decrease of migration index in all groups of subjects, turning to positive the reactions in lepromatous patients. The significance of these circulating factors, able to enhance or inhibit cell migration inhibition responses in patients and controls, is discussed.

Antigen-Antibody Complex↗
PubMed1999

Ras-transfection up-regulated HaCaT cell migration: inhibition by Marimastat.

Cell migration is an essential process in physiological and pathological conditions such as wound healing and tumor invasion. This phenomenon involves cell adhesion on the extracellular matrix mediated by integrins, and cell detachment promoted in part by metalloproteinases (MMPs). In the present study, the migration of two HaCaT-ras clones (metastatic or not), was compared with HaCaT cells, and normal human primary cultured keratinocytes. Using colloidal gold migration assay, the migration index on type I and type IV collagen was similar for primary cultured keratinocytes and HaCaT, whereas it was markedly higher for the HaCaT-ras clones. High motility of ras-transfected cells was confirmed from an in vitro wound healing assay. It was not correlated with changes in integrin expression or related to a different adhesion on extracellular matrix. The Marismastat (BB-2516), a MMP inhibitor, inhibited in a dose-dependent effect the migration in both assays, demonstrating the important role of MMPs in the migration process. Under our experimental conditions, MMP-1 activity was not detected in HaCaT and MMP-9 activity was secreted by these cells only after their stimulation by EGF. Here, MMP-2 was the major gelatinolytic activity secreted by all the cells and its secretion was markedly higher for HaCaT-nis clones compared with HaCaT. In addition, Western blotting results confirmed a higher expression of MMP-2 associated with a lower expression of TIMP-2 in HaCaT-ras compared with HaCaT. These results suggest that Ha-ras oncogene could be a stimulating factor of migration and might modified the balance between MMP-2 and TIMP-2 in keratinocyte cell lines.

Cell Adhesion↗
PubMed1997

Annexins II and V inhibit cell migration.

Cell motility is a crucial component involved in wound healing, development, and tumor metastasis. This study investigated whether extracellular annexins, members of a calcium- and phospholipid-binding family of proteins, play a role in the migration of Lewis lung carcinoma cells. Using assays for wound closure and migration through 8-micron pores, it was found that annexins II and V significantly (> 40%) inhibited migration of these highly metastatic cells. Additionally, anti-annexin II antibodies enhanced migration of these same cells in the wound closure assay, while an irrelevant antibody (anti-calmodulin) showed no effect. These effects may be due to annexin-membrane binding and inhibition of phospholipid movement that is necessary for the formation of membrane protrusions.

Animals↗
PubMed1980

Time-lapse cinematography of the capillary tube cell migration inhibition test.

The kinetics of human and guinea pig cell migration inhibition have been studied using time-lapse cinematography of cells migrating from capillary tubes. Guinea pig and human cells exhibit markedly different kinetics in the absence of inhibitors. Specific antigen causes a dose-related inhibition of migration for up to 60 h using guinea pig cells and a peak of inhibition after 18 h using the human leucocyte system. The timing of measurement of maximum activity more critical for the latter test. The kinetics of lymphokine generation have been examined and the migration inhibitory activity of the plant mitogen (PHA), a Kurloff cell product and a continuous cell line supernatant have been compared with the inhibitory profiles of lymphokine preparations and specific antigen.

Animals↗
PubMed2006

Sphingosine-1-phosphate inhibits cell migration and endothelial to mesenchymal cell transformation during cardiac development.

Sphingosine-1-phosphate (S1P) is a biologically active sphingolipid metabolite that exerts important effects on numerous cellular events via cell surface receptors, S1P(1-5). S1P influences differentiation, proliferation, and migration during vascular development. However, the effects of S1P signaling on early cardiac development are not well understood. To address this issue, we examined the expression of S1P regulatory enzymes and S1P receptors during cardiac development. We observed that enzymes that regulate S1P levels, sphingosine kinase and sphingosine-1-phosphate phosphatase, are expressed in the developing heart. In addition, RT-PCR revealed that four of the five known S1P receptors (S1P(1-4)) are also expressed in the developing heart. Next, effects of altered S1P levels on whole embryo and atrioventricular (AV) canal cultures were investigated. We demonstrate that inactivation of the S1P producing enzyme, sphingosine kinase, leads to cell death in cardiac tissue which is rescued by exogenous S1P treatment. Other experiments reveal that increased S1P concentration prevents alterations in cell morphology that are required for cell migration. This effect results in reduced cell migration and inhibited mesenchymal cell formation in AV canal cushion tissue. These data indicate that S1P, locally maintained within a specific concentration range, is an important and necessary component of early heart development.

Animals↗
PubMed1997

Inhibition of migration of endothelial cells by type V collagen and high molecular weight kininogens.

The failure of synthetic vascular grafts in humans is complex and related not only to the type of material but also to the accumulation of cellular and noncellular components onto or within the material. Proteins that adsorb on biomaterials such as vascular grafts may be involved in modulating cell function. Of these components, type V collagen and high molecular weight kininogens (HMWKs) are known to localize on the surface of vascular grafts. We have investigated the effect of type V collagen and HMWKs in the prevention of endothelialization of vascular prostheses by inhibiting cell migration. Inhibition of endothelial cell migration may lead to incomplete endothelialization and thus, failure of these devices. Various concentrations of type V collagen and HMWK solutions were placed at the bottom of 24 well tissue culture plates with porous membrane inserts (8 microns pore size) placed on top. Suspended human umbilical vein endothelial cells (HUVECs) were placed on top of the insert and incubated at 37 degrees C for 2 hours. Following incubation, the inserts were fixed and the cells that migrated through the pores were counted by microscopy. Our results showed that migration of endothelial cells was significantly inhibited in a dose dependent manner by type V collagen and HMWKs.

Cell Movement↗
PubMed2001

Increased filamin binding to beta-integrin cytoplasmic domains inhibits cell migration.

Multicellular animal development depends on integrins. These adhesion receptors link to the actin cytoskeleton, transmitting biochemical signals and force during cell migration and interactions with the extracellular matrix. Many integrin-cytoskeleton connections are formed by filamins and talin. The beta7 integrin tail binds strongly to filamin and supports less migration, fibronectin matrix assembly and focal adhesion formation than either the beta1D tail, which binds strongly to talin, or the beta1A tail, which binds modestly to both filamin and talin. To probe the role of filamin binding, we mapped the filamin-binding site of integrin tails and identified amino acid substitutions that led to selective loss of filamin binding to the beta7 tail and gain of filamin binding to the beta1A tail. These changes affected cell migration and membrane protrusions but not fibronectin matrix assembly or focal adhesion formation. Thus, tight filamin binding restricts integrin-dependent cell migration by inhibiting transient membrane protrusion and cell polarization.

Amino Acid Substitution↗
PubMed2002

RhoA inactivation inhibits cell migration but does not mediate the effects of polyamine depletion.

BACKGROUND & AIMS: Inhibition of RhoA activity and depletion of polyamines inhibits cell migration and causes changes in the actin cytoskeleton. In this article we have examined the effect of polyamine depletion on RhoA and evaluated these effects on cell migration. METHODS: Polyamines were depleted in intestinal epithelial cell (IEC)-6 cells by incubating them for 4 days with 5 mmol/L alpha-difluoromethylornithine (DFMO), which inhibits ornithine decarboxylase, the first rate-limiting enzyme in the synthesis of polyamines. IEC-6 cells were then transfected with vectors containing HA tags and constitutively active (HA-V14) or dominant-negative (HA-N19) RhoA with pcDNA3 (vector). RESULTS: DFMO caused a significant decrease in Rho levels in the cytoplasm and membranes of IEC-6 cells. This decrease was caused by an approximate 50% inhibition of RhoA protein synthesis. Neither the half-life of RhoA nor the level of RhoA messenger RNA (mRNA) was affected. HA-V14-RhoA cells migrated much more rapidly than vector-transfected cells, and HA-N19-RhoA cells exhibited almost no motility. The migration of HA-V14-RhoA cells, however, was inhibited markedly by polyamine depletion. Polyamine depletion did not affect the activity of RhoA in HA-V14-RhoA cells, but inhibited it dramatically in the vector-transfected cells. In the presence of DFMO, the HA-V14-RhoA cells lost stress fibers and gained the appearance of HA-N19-RhoA cells or wild-type cells treated with DFMO. CONCLUSIONS: First, polyamines are essential for the activity and synthesis and, therefore, normal levels of RhoA protein. Second, RhoA does not mediate the inhibitory effects of polyamine depletion on cell migration.

Animals↗
PubMed2005

Wisteria floribunda gall extract inhibits cell migration in mouse B16F1 melanoma cells by regulating CD44 expression and GTP-RhoA activity.

Extracts from galls grown on Wisteria floribunda are used as an anti-tumoral preparation in oriental traditional medicine. Here, we investigated the molecular mechanism of this anti-tumoral effect by first examining whether the extract inhibited cell migration in a B16 cell-based wound healing assay. The gall extract delayed wound healing in a dose- and time-dependent manner, indicating that one or more components of the fraction inhibited cell migration. Examination of two molecules known to be involved in metastasis, CD44, and RhoA-GTP, revealed that the gall extract decreased CD44 expression in a concentration-dependent manner, and also increased RhoA-GTP activity in comparison to untreated controls. Taken together, these results suggest that the Wisteria gall extract may inhibit cancer cell migration via inhibition of CD44 mRNA expression and activation of the GTP-RhoA protein.

Animals↗
PubMed1975

In vitro evaluation of cell-mediated immunity to Epstein-Barr herpesvirus by cell migration inhibition tests.

Migration of peripheral leukocytes in samples from sensitized [Epstein-Barr virus (EBV) antibody-positive] humans was greatly inhibited when challenged by antigen prepared from EBV-producing P3HR-1 cells but not by antigen prepared from EBV-nonproducing RAJI cells, EBV-negative human fibroblasts, or epithelial cells. Such inhibition was not observed when peripheral leuocytes from subjects or neonates not sensitized to EBV were challenged. Similar results were obtained in a two-stage test when the same leukocyte samples were challenged in vitro by antigen prepared from P3HR-1 cells and the cell-free supernatant was assayed for migration inhibition factor (MIF) in the guinea pig macrophage migration inhibition test; migration of guinea pig peritoneal exudate cells was greatly inhibited by the supernatant filtrates of leukocyte cultures only from subjects positive for EBV-antibody. Furthermore, this inhibitory effect was not observed if supernatant filtrates from leukocyte cultures challenged by antigens prepared from RAJI cells, fibroblasts, or epithelial cells were used. The EBV antigen transformed peripheral leukocytes and induced early antigen production in RAJI cells; however, a "killed" preparation (by UV irradiation) was sufficient for eliciting MIF production.

Antibodies, Viral↗
PubMed2004

Alpha1B-adrenoceptor signaling and cell motility: GTPase function of Gh/transglutaminase 2 inhibits cell migration through interaction with cytoplasmic tail of integrin alpha subunits.

A multifunctional enzyme, G(h), is a GTP-binding protein that couples to the alpha(1B)-adrenoreceptor and stimulates phospholipase C-delta1 but also displays transglutaminase 2 (TG2) activity. G(h)/TG2 has been implicated to play a role in cell motility. In this study we have examined which function of G(h)/TG2 is involved in this cellular response and the molecular basis. Treatment of human aortic smooth muscle cell with epinephrine inhibits migration to fibronectin and vitronectin, and the inhibition is blocked by the alpha(1)-adrenoreceptor antagonist prazosin or chloroethylclonidine. Up-regulation or overexpression of G(h)/TG2 in human aortic smooth muscle cells, DDT1-MF2, or human embryonic kidney cells, HEK 293 cells, results in inhibition of the migratory activity, and stimulation of the alpha(1B)-adrenoreceptor with the alpha(1) agonist further augments the inhibition of migration of human aortic smooth muscle cells and DDT1-MF2. G(h)/TG2 is coimmunoprecipitated by an integrin alpha(5) antibody and binds to the cytoplasmic tail peptide of integrins alpha(5), alpha(v), and alpha(IIb) subunits in the presence of guanosine 5'-3-O-(thio)triphosphate (GTPgammaS). Mutation of Lys-Arg residues in the GFFKR motif, present in the alpha(5)-tail, significantly reduces the binding of GTPgammaS-G(h)/TG2. Moreover, the motif-containing integrin alpha(5)-tail peptides block G(h)/TG2 coimmunoprecipitation and reverse the inhibition of the migratory activity of HEK 293 cells caused by overexpression G(h)/TG2. These results provide evidence that G(h) function initiates the modulation of cell motility via association of GTP-bound G(h)/TG2 with the GFFKR motif located in integrin alpha subunits.

Amino Acid Motifs↗
PubMed2002

Maspin inhibits cell migration in the absence of protease inhibitory activity.

Maspin is a member of the serpin family of protease inhibitors and is a tumor suppressor gene acting at the level of tumor invasion and metastasis. This in vivo activity correlates with the ability of maspin to inhibit cell migration in vitro. This behavior suggests that maspin inhibits matrix-degrading proteases, such as those of the plasminogen activation system, in a similar manner to the serpin PAI-1. However, there is controversy concerning the protease inhibitory activity of maspin. It is devoid of activity against a wide range of proteases, in common with other non-inhibitory serpins, but has recently been reported to inhibit plasminogen activators associated with cells and other biological surfaces (Sheng, S. J., Truong, B., Fredrickson, D., Wu, R. L., Pardee, A. B., and Sager, R. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 499-504; McGowen, R., Biliran, H., Jr., Sager, R., and Sheng, S. (2000) Cancer Res. 60, 4771-4778). We have compared the effects of maspin with those of PAI-1 in a range of situations in which plasminogen activation is potentiated, reflecting the biological context of this proteolytic system: urokinase-type plasminogen activator bound to its receptor on the surface of tumor cells, tissue-type plasminogen activator specifically bound to vascular smooth muscle cells, fibrin, and the prion protein. Maspin was found to have no inhibitory effect in any of these situations, in contrast to the efficient inhibition observed with PAI-1, but nevertheless maspin inhibited the migration of both tumor and vascular smooth muscle cells. We conclude that maspin is a non-inhibitory serpin and that protease inhibition does not account for its activity as a tumor suppressor.

Amino Acid Sequence↗
PubMed2004

Activation of protein kinase G is sufficient to induce apoptosis and inhibit cell migration in colon cancer cells.

The activation of protein kinase G (PKG) by cGMP has become of considerable interest as a novel molecular mechanism for the induction of apoptosis in cancer cells, because sulindac sulfone (exisulind, Aptosyn) and certain derivatives that inhibit cGMP-phosphodiesterases and thereby increase cellular levels of cGMP appear to induce apoptosis via this mechanism. However, other effects of these compounds have not been excluded, and the precise mechanism by which PKG activation induces apoptosis has not been elucidated in detail. To directly examine the effects of PKG on cell growth and apoptosis, we generated a series of mutants of PKG Ialpha: PKG IalphaS65D, a constitutively activated point mutant; PKG IalphaDelta, a constitutively activated N-terminal truncated mutant; and PKG IalphaK390R, a dominant-negative point mutant. A similar series of mutants of PKG Ibeta were also constructed (Deguchi et al., Mol. Cancer Ther., 1: 803-809, 2002). The present study demonstrates that when transiently expressed in SW480 colon cancer, the constitutively activated mutants of PKG Ibeta, and to a lesser extent PKG Ialpha, inhibit colony formation and induce apoptosis. We were not able to obtain derivatives of SW480 cells that stably expressed these constitutively activated mutants, presumably because of toxicity. However, derivatives that stably overexpressed wild-type PKG Ibeta displayed growth inhibition, whereas derivatives that stably expressed the dominant-negative mutant (KR) of PKG Ibeta grew more rapidly and were more resistant to Aptosyn-induced growth inhibition than vector control cells. Stable overexpression of PKG Ibeta was associated with decreased cellular levels of beta-catenin and cyclin D1 and increased levels of p21(CIP1). Reporter assays indicated that activation of PKG Ibeta inhibits the transcriptional activity of the cyclin D1 promoter. We also found that transient expression of the constitutively activated mutants of PKG Ibeta inhibited cell migration. Taken together, these results indicate that activation of PKG Ibeta is sufficient to inhibit growth and cell migration and induce apoptosis in human colon cancer cells and that these effects are associated with inhibition of the transcription of cyclin D1 and an increase in the expression of p21(CIP1).

Antineoplastic Agents↗
PubMed1993

Estramustine induces disorganization of microtubules, perinuclear retraction of vimentin and endoplasmatic reticulum, and inhibits cell migration.

The effects of the mitotic inhibitor estramustine on the cytoskeleton of DU 145 and AG 1518 cells were studied. Estramustine caused a partial disassembly of microtubules and withdrawal of microtubules from the cell periphery, disorganized microtubules and delayed regrowth of disassembled microtubules. It also induced a spheroid cellular morphology and affected cellular adhesion and survival. Sometimes microtubules seemed to be organized from several microtubule-organizing centers. The cytoskeleton-dependent cell migration was inhibited in the presence of estramustine and the microtubule-interacting vimentin and endoplasmatic reticulum retracted to the perinuclear area. Our results show that not only a complete disassembly of microtubules, but also disturbances of the microtubule network can have dramatic effects on microtubule-dependent processes and localization of cellular organelles. These effects could be of importance in the treatment of prostatic carcinoma with estramustine.

Cell Adhesion↗
PubMed2000

Amlexanox reversibly inhibits cell migration and proliferation and induces the Src-dependent disassembly of actin stress fibers in vitro.

Amlexanox binds S100A13 and inhibits the release of fibroblast growth factor 1 (FGF1). Because members of the S100 gene family are known to be involved with the function of the cytoskeleton, we examined the ability of amlexanox to modify the cytoskeleton and report that amlexanox induces a dramatic reduction in the presence of actin stress fibers and the appearance of a random, non-oriented distribution of focal adhesion sites. Correspondingly, amlexanox induces the complete and reversible non-apoptotic inhibition of cell migration and proliferation, and although amlexanox does not induce either the down-regulation of F-actin levels or the depolymerization of actin filaments, it does induce the tyrosine phosphorylation of cortactin, a Src substrate known to regulate actin bundling. In addition, a dominant negative form of Src is able to partially rescue cells from the effect of amlexanox on both the actin cytoskeleton and cell migration. In contrast, the inhibition of cell proliferation by amlexanox correlates with the inhibition of cyclin D1 expression without interference of the receptor tyrosine kinase/mitogen-activated protein kinase signaling pathway. Last, the ability of amlexanox to inhibit FGF1 release is reversible and correlates with the restoration of the actin cytoskeleton, suggesting a role for the actin cytoskeleton in the FGF1 release pathway.

3T3 Cells↗