Functional role of melanoma inhibitory activity in regulating invasion and metastasis of malignant melanoma cells in vivo

2001 ◽  
Vol 11 (4) ◽  
pp. 417-421 ◽  
Author(s):  
A. -K. Bosserhoff ◽  
B. Echtenacher ◽  
R. Hein ◽  
R. Buettner
Keyword(s):  
Malignant Melanoma ◽  
Inhibitory Activity ◽  
Functional Role ◽  
Melanoma Cells ◽  
Invasion And Metastasis ◽  
Melanoma Inhibitory Activity

scholarly journals Upregulation of HMG1 Leads to Melanoma Inhibitory Activity Expression in Malignant Melanoma Cells and Contributes to Their Malignancy Phenotype

2003 ◽  
Vol 23 (8) ◽  
pp. 2991-2998 ◽  
Author(s):  
Ina Poser ◽  
Michaela Golob ◽  
Reinhard Buettner ◽  
Anja K. Bosserhoff
Keyword(s):  
Transcription Factor ◽  
Malignant Melanoma ◽  
Inhibitory Activity ◽  
Melanoma Cells ◽  
Peptide Sequence ◽  
Transcriptional Level ◽  
Promoter Element ◽  
Promoter Activation ◽  
Mobility Shift ◽  
Melanoma Inhibitory Activity

ABSTRACT Malignant transformation of melanocytes to melanoma cells closely parallels activation of melanoma inhibitory activity (MIA) expression. We have previously shown that upregulation of MIA occurs on a transcriptional level and involves the highly conserved region (HCR) promoter element. We further observed that the HCR element interacts with the melanoma-associated transcription factor (MATF) and thereby confers strong promoter activation. In this study we identify the peptide sequence of MATF and show that it is identical with the transcription factor HMG1. HMG1 was upregulated in malignant melanoma cells and further activated by hypophosphorylation. Stable antisense-HMG1 expression in melanoma cells led to the reduction of MIA promoter activity and protein expression, indicating that HMG1 is a potent regulator of MIA expression. Interestingly, chromatin immunoprecipitation and electrophoretic mobility shift experiments indicated that HMG1 and the NF-κB family member p65 both interact and bind to the HCR promoter element. In summary, our study proves HMG1 and p65 to be important factors in MIA regulation and melanoma progression.

scholarly journals Overexpression of melanoma inhibitory activity (MIA) enhances extravasation and metastasis of A-mel 3 melanoma cells in vivo

2000 ◽  
Vol 83 (9) ◽  
pp. 1216-1222 ◽  
Author(s):  
M Guba ◽  
A-K Bosserhoff ◽  
M Steinbauer ◽  
C Abels ◽  
M Anthuber ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Melanoma Cells ◽  
Melanoma Inhibitory Activity

scholarly journals Active Detachment Involves Inhibition of Cell-Matrix Contacts of Malignant Melanoma Cells by Secretion of Melanoma Inhibitory Activity

2003 ◽  
Vol 83 (11) ◽  
pp. 1583-1594 ◽  
Author(s):  
Anja-Katrin Bosserhoff ◽  
Raphael Stoll ◽  
Jonathan P Sleeman ◽  
Frauke Bataille ◽  
Reinhard Buettner ◽  
...  
Keyword(s):  
Malignant Melanoma ◽  
Inhibitory Activity ◽  
Melanoma Cells ◽  
Cell Matrix ◽  
Melanoma Inhibitory Activity

scholarly journals The phosphatase Shp1 interacts with and dephosphorylates cortactin to inhibit invadopodia function

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Alessia Varone ◽  
Chiara Amoruso ◽  
Marcello Monti ◽  
Manpreet Patheja ◽  
Adelaide Greco ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Tyrosine Phosphatase ◽  
Melanoma Cells ◽  
Matrix Degradation ◽  
Extracellular Matrix Degradation ◽  
Invadopodia Formation ◽  
Interference Rna

Abstract Background Invadopodia are actin-based cell-membrane protrusions associated with the extracellular matrix degradation accompanying cancer invasion. The elucidation of the molecular mechanisms leading to invadopodia formation and activity is central for the prevention of tumor spreading and growth. Protein tyrosine kinases such as Src are known to regulate invadopodia assembly, little is however known on the role of protein tyrosine phosphatases in this process. Among these enzymes, we have selected the tyrosine phosphatase Shp1 to investigate its potential role in invadopodia assembly, due to its involvement in cancer development. Methods Co-immunoprecipitation and immunofluorescence studies were employed to identify novel substrate/s of Shp1AQ controlling invadopodia activity. The phosphorylation level of cortactin, the Shp1 substrate identified in this study, was assessed by immunoprecipitation, in vitro phosphatase and western blot assays. Short interference RNA and a catalytically-dead mutant of Shp1 expressed in A375MM melanoma cells were used to evaluate the role of the specific Shp1-mediated dephosphorylation of cortactin. The anti-invasive proprieties of glycerophosphoinositol, that directly binds and regulates Shp1, were investigated by extracellular matrix degradation assays and in vivo mouse model of metastasis. Results The data show that Shp1 was recruited to invadopodia and promoted the dephosphorylation of cortactin at tyrosine 421, leading to an attenuated capacity of melanoma cancer cells to degrade the extracellular matrix. Controls included the use of short interference RNA and catalytically-dead mutant that prevented the dephosphorylation of cortactin and hence the decrease the extracellular matrix degradation by melanoma cells. In addition, the phosphoinositide metabolite glycerophosphoinositol facilitated the localization of Shp1 at invadopodia hence promoting cortactin dephosphorylation. This impaired invadopodia function and tumor dissemination both in vitro and in an in vivo model of melanomas. Conclusion The main finding here reported is that cortactin is a specific substrate of the tyrosine phosphatase Shp1 and that its phosphorylation/dephosphorylation affects invadopodia formation and, as a consequence, the ability of melanoma cells to invade the extracellular matrix. Shp1 can thus be considered as a regulator of melanoma cell invasiveness and a potential target for antimetastatic drugs.

scholarly journals Melanoma Inhibitory Activity and regional lymph node status in malignant melanoma patients

2015 ◽  
Vol 13 (Suppl 1) ◽  
pp. P11
Author(s):  
Angela Sandru ◽  
Silviu Voinea ◽  
Eugenia Panaitescu ◽  
Madalina Bolovan ◽  
Adina Stanciu ◽  
...  
Keyword(s):  
Lymph Node ◽  
Malignant Melanoma ◽  
Inhibitory Activity ◽  
Regional Lymph Node ◽  
Lymph Node Status ◽  
Node Status ◽  
Melanoma Inhibitory Activity ◽  
Melanoma Patients

scholarly journals WNT-5A regulates TGF-β-related activities in liver fibrosis

2017 ◽  
Vol 312 (3) ◽  
pp. G219-G227 ◽  
Author(s):  
Leonie Beljaars ◽  
Sara Daliri ◽  
Christa Dijkhuizen ◽  
Klaas Poelstra ◽  
Reinoud Gosens
Keyword(s):  
Liver Fibrosis ◽  
Functional Role ◽  
Collagen Type ◽  
Collagen Type I ◽  
Matrix Proteins ◽  
Type I ◽  
Human Livers

WNT-5A is a secreted growth factor that belongs to the noncanonical members of the Wingless-related MMTV-integration family. Previous studies pointed to a connection between WNT-5A and the fibrogenic factor TGF-β warranting further studies into the functional role of WNT-5A in liver fibrosis. Therefore, we studied WNT-5A expressions in mouse and human fibrotic livers and examined the relation between WNT-5A and various fibrosis-associated growth factors, cytokines, and extracellular matrix proteins. WNT-5A gene and protein expressions were significantly increased in fibrotic mouse and human livers compared with healthy livers. Regression or therapeutic intervention in mice resulted in decreased hepatic WNT-5A levels paralleled by lower collagen levels. Immunohistochemical analysis showed WNT-5A staining in fibrotic septa colocalizing with desmin staining indicating WNT-5A expression in myofibroblasts. In vitro studies confirmed WNT-5A expression in this cell type and showed that TGF-β significantly enhanced WNT-5A expression in contrast to PDGF-BB and proinflammatory cytokines IL-1β and TNF-α. Additionally, TGF-β induces the expression of the WNT receptors FZD2 and FZD8. After silencing of WNT-5A, reduced levels of collagen type I, vimentin, and fibronectin in TGF-β-stimulated myofibroblasts were measured compared with nonsilencing siRNA-treated controls. Interestingly, the antifibrotic cytokine IFNγ suppressed WNT-5A in vitro and in vivo. IFNγ-treated fibrotic mice showed significantly less WNT-5A expression compared with untreated fibrotic mice. In conclusion, WNT-5A paralleled collagen I levels in fibrotic mouse and human livers. WNT-5A expression in myofibroblasts is induced by the profibrotic factor TGF-β and plays an important role in TGF-β-induced regulation of fibrotic matrix proteins, whereas its expression can be reversed upon treatment, both in vitro and in vivo. NEW & NOTEWORTHY This study describes the localization and functional role of WNT-5A in human and mouse fibrotic livers. Hepatic WNT-5A expression parallels collagen type I expression. In vivo and in vitro, the myofibroblasts were identified as the key hepatic cells producing WNT-5A. WNT-5A is under control of TGF-β and its activities are primarily profibrotic.

scholarly journals The Induction of Apoptosis in A375 Malignant Melanoma Cells bySutherlandia frutescens

2016 ◽  
Vol 2016 ◽  
pp. 1-14 ◽  
Author(s):  
Nicola B. van der Walt ◽  
Zahra Zakeri ◽  
Marianne J. Cronjé
Keyword(s):  
Malignant Melanoma ◽  
Basic Mechanism ◽  
Melanoma Cells ◽  
Caspase Activation ◽  
Nuclear Condensation ◽  
Induced Apoptosis ◽  
Apoptosis Inducing Factor ◽  
A375 Melanoma Cell Line ◽  
A375 Cells

Sutherlandia frutescensis a medicinal plant indigenous to Southern Africa and is commonly known as the “cancer bush.” This plant has traditionally been used for the treatment of various ailments, although it is best known for its claims of activity against “internal” cancers. Here we report on its effect on melanoma cells. The aim of this study was to investigate whether an extract ofS. frutescenscould induce apoptosis in the A375 melanoma cell line and to outline the basic mechanism of action.S. frutescensextract induced apoptosis in A375 cells as evidenced by morphological features of apoptosis, phosphatidylserine exposure, nuclear condensation, caspase activation, and the release of cytochromecfrom the mitochondria. Studies in the presence of a pan-caspase inhibitor allude to caspase-independent cell death, which appeared to be mediated by the apoptosis inducing factor. Taken together, the results of this study show thatS. frutescensextract is effective in inducing apoptosis in malignant melanoma cells and indicates that furtherin vivomechanistic studies may be warranted.

scholarly journals Cathepsin G-dependent platelet stimulation by activated polymorphonuclear leukocytes and its inhibition by antiproteinases: role of P-selectin-mediated cell-cell adhesion

Blood ◽  
1993 ◽  
Vol 81 (11) ◽  
pp. 2947-2957 ◽  
Author(s):  
V Evangelista ◽  
P Piccardoni ◽  
JG White ◽  
G de Gaetano ◽  
C Cerletti
Keyword(s):  
Functional Role ◽  
Polymorphonuclear Leukocytes ◽  
Platelet Adhesion ◽  
Inhibitory Effect ◽  
Serotonin Release ◽  
Cathepsin G ◽  
Inhibitory Antibody ◽  
Neuraminidase Treatment

Human PMN stimulated by fMLP are able to activate coincubated, autologous platelets. Cathepsin G, a neutral serine protease stored in the azurophilic granules of PMN, is the major platelet activator in this system. We previously proposed that shear-induced close PMN- platelet contact creates the conditions for which cathepsin G activity on platelets is protected against antiproteinases. The aim of this study was to investigate the adhesive mechanisms, possibly creating between PMN and platelet membranes the microenvironment in which cathepsin G, discharged from stimulated PMN onto adherent platelets, is protected against antiproteinases. Microscopic examination showed that under conditions of high shear, 71.3% +/- 6.1% of PMN were associated to platelets forming small clumps. This percentage decreased to 10% +/- 2% and 13% +/- 4%, respectively, in the presence of an inhibitory antibody to P-selectin or 20 mmol/L mannose-1-phosphate and to 10.8% +/- 3.7% when cells were not stirred. Similarly, PMN pretreatment with neuraminidase abolished PMN binding to platelets. These results indicate that P-selectin mediates PMN-platelet adhesion occurring before PMN stimulation. Prevention of PMN-platelet contact significantly potentiated the inhibitory effect of alpha 1-protease inhibitor on subsequent cathepsin G-induced platelet serotonin release. Because anti-P-selectin antibody, mannose-1-phosphate, and neuraminidase treatment of PMN did not modify PMN-induced platelet activation in the absence of antiproteinases, it is suggested that P- selectin-mediated PMN-platelet adhesion results in the formation of a sequestered microenvironment between cell membranes, in which higher amounts of antiproteinases are required to prevent the activity of released cathepsin G. These data add a new functional role to P- selectin-mediated PMN-platelet adhesion that could be important in vivo because of the presence of antiproteinases in plasma.

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