Inhibition of glutaminyl cyclase attenuates cell migration modulated by monocyte chemoattractant proteins

2012 ◽  
Vol 442 (2) ◽  
pp. 403-412 ◽  
Author(s):  
Yi-Ling Chen ◽  
Kai-Fa Huang ◽  
Wen-Chih Kuo ◽  
Yan-Chung Lo ◽  
Yu-May Lee ◽  
...  
Keyword(s):  
Cell Migration ◽  
Inhibitory Effect ◽  
Glutaminyl Cyclase ◽  
Monocyte Chemoattractant ◽  
Monocyte Migration ◽  
Similar Inhibitory Effect ◽  
And Migration ◽  
Interfering Rna

QC (glutaminyl cyclase) catalyses the formation of N-terminal pGlu (pyroglutamate) in peptides and proteins. pGlu formation in chemoattractants may participate in the regulation of macrophage activation and migration. However, a clear molecular mechanism for the regulation is lacking. The present study examines the role of QC-mediated pGlu formation on MCPs (monocyte chemoattractant proteins) in inflammation. We demonstrated in vitro the pGlu formation on MCPs by QC using MS. A potent QC inhibitor, PBD150, significantly reduced the N-terminal uncyclized-MCP-stimulated monocyte migration, whereas pGlu-containing MCP-induced cell migration was unaffected. QC small interfering RNA revealed a similar inhibitory effect. Lastly, we demonstrated that inhibiting QC can attenuate cell migration by lipopolysaccharide. These results strongly suggest that QC-catalysed N-terminal pGlu formation of MCPs is required for monocyte migration and provide new insights into the role of QC in the inflammation process. Our results also suggest that QC could be a drug target for some inflammatory disorders.

The integrin alphavbeta6 is critical for keratinocyte migration on both its known ligand, fibronectin, and on vitronectin

1998 ◽  
Vol 111 (15) ◽  
pp. 2189-2195 ◽  
Author(s):  
X. Huang ◽  
J. Wu ◽  
S. Spong ◽  
D. Sheppard
Keyword(s):  
Cell Migration ◽  
Tissue Injury ◽  
Critical Role ◽  
Cell Behavior ◽  
Wild Type ◽  
Migration Assays ◽  
And Migration ◽  
Hepatocyte Growth

The integrin alphavbeta6 is expressed on a variety of epithelial cells during dynamic processes including organogenesis, tissue injury and malignant transformation. However, because of the lack of tools to specifically inhibit the function of this integrin, little is known about its effects on cell behavior. To directly examine the role of this integrin in cell migration, we used keratinocytes derived from wild-type mice or mice expressing a null mutation in the beta6 subunit (beta6-/-) to perform migration assays in vitro. Migration on the known alphavbeta6 ligand, fibronectin was reduced in keratinocytes from beta6-/- mice. Interestingly, keratinocytes from beta6-/- mice also demonstrated markedly reduced migration on vitronectin, a protein not previously known to be a ligand for alphavbeta6. An anti-alphavbeta6 monoclonal antibody 10D5, generated by immunization of beta6-/- mice with murine keratinocytes, inhibited adhesion and migration of wild-type keratinocyte on both vitronectin and fibronectin to levels similar to those seen with keratinocytes from beta6-/- mice. alphavbeta6-mediated migration on both ligands was dramatically augmented by treatment with phorbol myrisate acetate (PMA) or with hepatocyte growth factor, and augmentation of migration by either stimulus could be abolished by the PKC inhibitor GF109203X, suggesting a critical role for PKC in enhancement of alphavbeta6-mediated cell migration.

scholarly journals Myo1g is required for efficient adhesion and migration of activated B lymphocytes to inguinal lymph nodes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
D. Cruz-Zárate ◽  
O. López-Ortega ◽  
D. A. Girón-Pérez ◽  
A. M. Gonzalez-Suarez ◽  
J. L. García-Cordero ◽  
...  
Keyword(s):  
Cell Migration ◽  
Lymph Node ◽  
B Lymphocytes ◽  
Dynamic Process ◽  
Inguinal Lymph Node ◽  
Cytoskeletal Remodeling ◽  
And Migration

AbstractCell migration is a dynamic process that involves adhesion molecules and the deformation of the moving cell that depends on cytoskeletal remodeling and actin-modulating proteins such as myosins. In this work, we analyzed the role of the class I Myosin-1 g (Myo1g) in migratory processes of LPS + IL-4 activated B lymphocytes in vivo and in vitro. In vivo, the absence of Myo1g reduced homing of activated B lymphocytes into the inguinal lymph node. Using microchannel chambers and morphology analysis, we found that the lack of Myo1g caused adhesion and chemotaxis defects. Additionally, deficiency in Myo1g causes flaws in adopting a migratory morphology. Our results highlight the importance of Myo1g during B cell migration.

scholarly journals Filamin-A is required to mediate SST2 effects in pancreatic neuroendocrine tumours

2016 ◽  
Vol 23 (3) ◽  
pp. 181-190 ◽  
Author(s):  
Eleonora Vitali ◽  
Valeria Cambiaghi ◽  
Alessandro Zerbi ◽  
Carlo Carnaghi ◽  
Piergiuseppe Colombo ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cell Adhesion ◽  
Cell Line ◽  
Neuroendocrine Tumours ◽  
Somatostatin Receptor ◽  
Inhibitory Effect ◽  
Filamin A ◽  
Pancreatic Neuroendocrine Tumours

Somatostatin receptor type 2 (SST2) is the main pharmacological target of somatostatin (SS) analogues widely used in patients with pancreatic neuroendocrine tumours (P-NETs), this treatment being ineffective in a subset of patients. Since it has been demonstrated that Filamin A (FLNA) is involved in mediating GPCR expression, membrane anchoring and signalling, we investigated the role of this cytoskeleton protein in SST2 expression and signalling, angiogenesis, cell adhesion and cell migration in human P-NETs and in QGP1 cell line. We demonstrated that FLNA silencing was not able to affect SST2 expression in P-NET cells in basal conditions. Conversely, a significant reduction in SST2 expression (−43±21%, P<0.05 vs untreated cells) was observed in FLNA silenced QGP1 cells after long term SST2 activation with BIM23120. Moreover, the inhibitory effect of BIM23120 on cyclin D1 expression (−46±18%, P<0.05 vs untreated cells), P-ERK1/2 levels (−42±14%; P<0.05 vs untreated cells), cAMP accumulation (−24±3%, P<0.05 vs untreated cells), VEGF expression (−31±5%, P<0.01 vs untreated cells) and in vitro release (−40±24%, P<0.05 vs untreated cells) was completely lost after FLNA silencing. Interestingly, BIM23120 promoted cell adhesion (+86±45%, P<0.05 vs untreated cells) and inhibited cell migration (−24±2%, P<0.00001 vs untreated cells) in P-NETs cells and these effects were abolished in FLNA silenced cells. In conclusion, we demonstrated that FLNA plays a crucial role in SST2 expression and signalling, angiogenesis, cell adhesion and cell migration in P-NETs and in QGP1 cell line, suggesting a possible role of FLNA in determining the different responsiveness to SS analogues observed in P-NET patients.

Effect of Dipyridamole on Spontaneous Platelet Aggregation in Whole Blood Decreases with the Time After Venepuncture: Evidence for the Role of ADP

1987 ◽  
Vol 58 (02) ◽  
pp. 744-748 ◽  
Author(s):  
A R Saniabadi ◽  
G D O Lowe ◽  
J C Barbenel ◽  
C D Forbes
Keyword(s):  
Platelet Aggregation ◽  
Correlation Coefficient ◽  
Whole Blood ◽  
Blood Platelet ◽  
Inhibitory Effect ◽  
Time Interval ◽  
Adp Receptor ◽  
Spontaneous Platelet Aggregation

SummarySpontaneous platelet aggregation (SPA) was studied in human whole blood at 3, 5, 10, 20, 30, 40 and 60 minutes after venepuncture. Using a whole blood platelet counter, SPA was quantified by measuring the fall in single platelet count upon rollermixing aliquots of citrated blood at 37° C. The extent of SPA increased with the time after venepuncture, with a correlation coefficient of 0.819. The inhibitory effect of dipyridamole (Dipy) on SPA was studied: (a) 10 μM at each time interval; (b) 0.5-100 μM at 3 and 30 minutes and (c) 15 μM in combination with 100 μM adenosine, 8 μM 2-chloroadenosine (2ClAd, an ADP receptor blocker) and 50 μM aspirin. There was a rapid decrease in the inhibitory effect of Dipy with the time after venepuncture; the correlation coefficient was -0.533. At all the concentrations studied, Dipy was more effective at 3 minutes than at 30 minutes after venepuncture. A combination of Dipy with adenosine, 2ClAd or aspirin was a more effective inhibitor of SPA than either drug alone. However, when 15 μM Dipy and 10 μM Ad were added together, the inhibitory effect of Dipy was not increased significantly, suggesting that Dipy inhibits platelet aggregation independent of Ad. The increase in SPA with the time after venepuncture was abolished when blood was taken directly into the anticoagulant containing 5 μM 2ClAd. It is suggested that ADP released from the red blood cells is responsible for the increased platelet aggregability with the time after venepuncture and makes a serious contribution to the artifacts of in vitro platelet function studies.

Knockout of Ajuba Attenuates the Growth and Migration of Hepatocellular Carcinoma Cells

2020 ◽  
Vol 160 (11-12) ◽  
pp. 650-658
Author(s):  
Yichen Le ◽  
Yi He ◽  
Meirong Bai ◽  
Ying Wang ◽  
Jiaxue Wu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Growth ◽  
Cancer Progression ◽  
Normal Liver ◽  
Cell Growth And Migration ◽  
And Migration ◽  
Hcc Cells

Ajuba has been found to be mutated or aberrantly regulated in several human cancers and plays important roles in cancer progression via different signaling pathways. However, little is known about the role of Ajuba in hepatocellular carcinoma (HCC). Here, we found an upregulation of Ajuba expression in HCC tissues compared with normal liver tissues, while a poor prognosis was observed in HCC patients with high Ajuba expression. Knockout of Ajuba in HCC cells inhibited cell growth in vitro and in vivo, suppressed cell migration, and enhanced the cell apoptosis under stress. Moreover, re-expression of Ajuba in Ajuba-deficient cells could restore the phenotype of Ajuba-deficient cells. In conclusion, these results indicate that Ajuba is upregulated in HCC and promotes cell growth and migration of HCC cells, suggesting that Ajuba could possibly be a new target for HCC diagnosis and treatment.

scholarly journals Cyclooxygenase Inhibition Alters Proliferative, Migratory, and Invasive Properties of Human Glioblastoma Cells In Vitro

2021 ◽  
Vol 22 (9) ◽  
pp. 4297
Author(s):  
Matthew Thomas Ferreira ◽  
Juliano Andreoli Miyake ◽  
Renata Nascimento Gomes ◽  
Fábio Feitoza ◽  
Pollyana Bulgarelli Stevannato ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cell Biology ◽  
Gelatin Zymography ◽  
Viable Cell ◽  
Cell Counting ◽  
Gelatinolytic Activity ◽  
Ep4 Receptor ◽  
And Migration ◽  
Proliferation And Migration

Prostaglandin E2 (PGE2) is known to increase glioblastoma (GBM) cell proliferation and migration while cyclooxygenase (COX) inhibition decreases proliferation and migration. The present study investigated the effects of COX inhibitors and PGE2 receptor antagonists on GBM cell biology. Cells were grown with inhibitors and dose response, viable cell counting, flow cytometry, cell migration, gene expression, Western blotting, and gelatin zymography studies were performed. The stimulatory effects of PGE2 and the inhibitory effects of ibuprofen (IBP) were confirmed in GBM cells. The EP2 and EP4 receptors were identified as important mediators of the actions of PGE2 in GBM cells. The concomitant inhibition of EP2 and EP4 caused a significant decrease in cell migration which was not reverted by exogenous PGE2. In T98G cells exogenous PGE2 increased latent MMP2 gelatinolytic activity. The inhibition of COX1 or COX2 caused significant alterations in MMP2 expression and gelatinolytic activity in GBM cells. These findings provide further evidence for the importance of PGE2 signalling through the EP2 and the EP4 receptor in the control of GBM cell biology. They also support the hypothesis that a relationship exists between COX1 and MMP2 in GBM cells which merits further investigation as a novel therapeutic target for drug development.

scholarly journals Amphetamine-Decreased Progesterone and Estradiol Release in Rat Granulosa Cells: The Regulatory Role of cAMP- and Ca2+-Mediated Signaling Pathways

Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 493
Author(s):  
 Chung-Yu Chen ◽  
Chien-Rung Chen ◽  
Chiao-Nan Chen ◽  
Paulus S. Wang ◽  
Toby Mündel ◽  
...  
Keyword(s):  
Granulosa Cells ◽  
Prostaglandin F2α ◽  
Inhibitory Effect ◽  
Inhibitory Effects ◽  
Steroidogenic Enzyme ◽  
Estradiol Secretion ◽  
Basal Release ◽  
Ca2 Channels

The purpose of this study is to evaluate the amphetamine effects on progesterone and estradiol production in rat granulosa cells and the underlying cellular regulatory mechanisms. Freshly dispersed rat granulosa cells were cultured with various test drugs in the presence of amphetamine, and the estradiol/progesterone production and the cytosolic cAMP level were measured. Additionally, the cytosolic-free Ca2+ concentrations ([Ca2+]i) were measured to examine the role of Ca2+ influx in the presence of amphetamine. Amphetamine in vitro inhibited both basal and porcine follicle-stimulating hormone-stimulated estradiol/progesterone release, and amphetamine significantly decreased steroidogenic enzyme activities. Adding 8-Bromo-cAMP did not recover the inhibitory effects of amphetamine on progesterone and estradiol release. H89 significantly decreased progesterone and estradiol basal release but failed to enhance a further amphetamine inhibitory effect. Amphetamine was capable of further suppressing the release of estradiol release under the presence of nifedipine. Pretreatment with the amphetamine for 2 h decreased the basal [Ca2+]i and prostaglandin F2α-stimulated increase of [Ca2+]i. Amphetamine inhibits progesterone and estradiol secretion in rat granulosa cells through a mechanism involving decreased PKA-downstream steroidogenic enzyme activity and L-type Ca2+ channels. Our current findings show that it is necessary to study the possibility of amphetamine perturbing reproduction in females.

scholarly journals Progression and Differentiation of Alveolar Rhabdomyosarcoma Is Regulated by PAX7 Transcription Factor—Significance of Tumor Subclones

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1870
Author(s):  
Klaudia Skrzypek ◽  
Grażyna Adamek ◽  
Marta Kot ◽  
Bogna Badyra ◽  
Marcin Majka
Keyword(s):  
Transcription Factor ◽  
Cell Lines ◽  
Migration Activity ◽  
Id Proteins ◽  
Rh30 Cell ◽  
Str Profile ◽  
And Migration

Rhabdomyosarcoma (RMS), is the most frequent soft tissue tumor in children that originates from disturbances in differentiation process. Mechanisms leading to the development of RMS are still poorly understood. Therefore, by analysis of two RMS RH30 cell line subclones, one subclone PAX7 negative, while the second one PAX7 positive, and comparison with other RMS cell lines we aimed at identifying new mechanisms crucial for RMS progression. RH30 subclones were characterized by the same STR profile, but different morphology, rate of proliferation, migration activity and chemotactic abilities in vitro, as well as differences in tumor morphology and growth in vivo. Our analysis indicated a different level of expression of adhesion molecules (e.g., from VLA and ICAM families), myogenic microRNAs, such as miR-206 and transcription factors, such as MYOD, MYOG, SIX1, and ID. Silencing of PAX7 transcription factor with siRNA confirmed the crucial role of PAX7 transcription factor in proliferation, differentiation and migration of RMS cells. To conclude, our results suggest that tumor cell lines with the same STR profile can produce subclones that differ in many features and indicate crucial roles of PAX7 and ID proteins in the development of RMS.

scholarly journals Role of the V1G1 subunit of V-ATPase in breast cancer cell migration

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Maria De Luca ◽  
Roberta Romano ◽  
Cecilia Bucci
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Cell Motility ◽  
Cancer Progression ◽  
Tumor Formation ◽  
Downstream Signaling ◽  
Late Endosomes ◽  
Intracellular Compartments

AbstractV-ATPase is a large multi-subunit complex that regulates acidity of intracellular compartments and of extracellular environment. V-ATPase consists of several subunits that drive specific regulatory mechanisms. The V1G1 subunit, a component of the peripheral stalk of the pump, controls localization and activation of the pump on late endosomes and lysosomes by interacting with RILP and RAB7. Deregulation of some subunits of the pump has been related to tumor invasion and metastasis formation in breast cancer. We observed a decrease of V1G1 and RAB7 in highly invasive breast cancer cells, suggesting a key role of these proteins in controlling cancer progression. Moreover, in MDA-MB-231 cells, modulation of V1G1 affected cell migration and matrix metalloproteinase activation in vitro, processes important for tumor formation and dissemination. In these cells, characterized by high expression of EGFR, we demonstrated that V1G1 modulates EGFR stability and the EGFR downstream signaling pathways that control several factors required for cell motility, among which RAC1 and cofilin. In addition, we showed a key role of V1G1 in the biogenesis of endosomes and lysosomes. Altogether, our data describe a new molecular mechanism, controlled by V1G1, required for cell motility and that promotes breast cancer tumorigenesis.

scholarly journals Suppressive Role of Bam32/DAPP1 in Chemokine-Induced Neutrophil Recruitment

2021 ◽  
Vol 22 (4) ◽  
pp. 1825
Author(s):  
Li Hao ◽  
Aaron J. Marshall ◽  
Lixin Liu
Keyword(s):  
Small Gtpases ◽  
Neutrophil Recruitment ◽  
Neutrophil Chemotaxis ◽  
Wild Type ◽  
Adaptor Molecule ◽  
Geranylgeranyltransferase I ◽  
And Migration ◽  
Rap1 Activation

Bam32 (B cell adaptor molecule of 32 kDa) functions in the immune responses of various leukocytes. However, the role of neutrophil Bam32 in inflammation is entirely unknown. Here, we determined the role of Bam32 in chemokine CXCL2-induced neutrophil chemotaxis in three mouse models of neutrophil recruitment. By using intravital microscopy in the mouse cremaster muscle, we found that transmigrated neutrophil number, neutrophil chemotaxis velocity, and total neutrophil chemotaxis distance were increased in Bam32−/− mice when compared with wild-type (WT) mice. In CXCL2-induced mouse peritonitis, the total emigrated neutrophils were increased in Bam32−/− mice at 2 but not 4 h. The CXCL2-induced chemotaxis distance and migration velocity of isolated Bam32−/− neutrophils in vitro were increased. We examined the activation of small GTPases Rac1, Rac2, and Rap1; the levels of phospho-Akt2 and total Akt2; and their crosstalk with Bam32 in neutrophils. The deficiency of Bam32 suppressed Rap1 activation without changing the activation of Rac1 and Rac2. The pharmacological inhibition of Rap1 by geranylgeranyltransferase I inhibitor (GGTI298) increased WT neutrophil chemotaxis. In addition, the deficiency of Bam32, as well as the inhibition of Rap1 activation, increased the levels of CXCL2-induced Akt1/2 phosphorylation at Thr308/309 in neutrophils. The inhibition of Akt by SH-5 attenuated CXCL2-induced adhesion and emigration in Bam32−/− mice. Together, our results reveal that Bam32 has a suppressive role in chemokine-induced neutrophil chemotaxis by regulating Rap1 activation and that this role of Bam32 in chemokine-induced neutrophil recruitment relies on the activation of PI3K effector Akt.

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