scholarly journals The mechanosensitive TRPV2 calcium channel controls melanoma invasiveness and metastatic potential.

2021 ◽  
Author(s):  
Kenji F Shoji ◽  
Elsa Bayet ◽  
Dahiana Le Devedec ◽  
Aude Mallavialle ◽  
Severine Marionneau-lambot ◽  
...  
Keyword(s):  
Calcium Channel ◽  
Metastatic Melanoma ◽  
Metastatic Potential ◽  
Melanoma Cells ◽  
Melanoma Tumor ◽  
Advanced Malignancy ◽  
In Vitro Motility ◽  
Cytoskeleton Remodeling

Discovery of therapeutic targets against metastasis is of primary importance since being the main cause of cancer-related death. Deregulation of calcium homeostasis has been involved in numerous cellular metastatic behaviors, although the molecular determinants supporting these processes remain often unclear. Here, we showed that the expression of the plasma membrane TRPV2 calcium channel is a prominent feature in melanoma progression and dissemination. In fact, TRPV2 activity was sufficient to confer an invasive phenotype to non-invasive melanoma cells. Conversely, the invasive and migratory potential of highly metastatic melanoma cells was abolished upon TRPV2 silencing. Mechanistically, TRPV2 supports melanoma cells aggressiveness by being a new regulator of the calpain-dependent maturation of focal adhesion, and actin cytoskeleton remodeling. Finally, TRPV2 overexpression is a marker of advanced malignancy and bad prognosis in human melanoma tumor samples. Altogether, TRPV2-induced Ca2+ signaling orchestrates in vitro motility and invasiveness of melanoma cells, as well as in vivo metastatic melanoma tumors dissemination.

scholarly journals CCN4 shifts melanoma cells from a fragile proliferative state to a resilient metastatic state

2018 ◽  
Author(s):  
Wentao Deng ◽  
Audry Fernandez ◽  
Sarah L. McLaughlin ◽  
David J. Klinke
Keyword(s):  
Cell Growth ◽  
Cell Survival ◽  
Intracellular Signaling ◽  
Metastatic Potential ◽  
Melanoma Cells ◽  
Culture Conditions ◽  
Matricellular Protein ◽  
Melanoma Progression

ABSTRACTWhile deregulated intracellular signaling initiates melanoma, intercellular crosstalk within the tumor microenvironment, often coordinated by soluble factors, is essential for melanoma progression and metastasis. One such secreted matricellular protein, cellular communication network factor 4 (CCN4), stimulates metastasis in other malignancies. Here, we report that CCN4 expression is associated progressively with reduced overall survival in patients with primary melanomas. To reveal the roles of CCN4 in melanoma progression, we used mouse melanoma models and knocked outCcn4using a homology-directed repair CRISPR/CAS9 system to generate pools ofCcn4-knockout cells.In vitroassays supported previous findings using clones generated using a double nickase-based CRISPR/CAS9 system that CCN4 promoted an epithelial – mesenchymal-like transition in melanoma cells and stimulated invasion and metastasis. We also found that, whileCcn4knockout enhanced cell growth in optimal 2D culture conditions, the knockout suppressed certain cell survival signaling pathways and rendered cells less resistant to stress conditions. Tumor cell growth assays at sub-optimal conditionsin vitro, quantitative analysis of tumor growth assaysin vivo,and transcriptomics analysis of human melanoma cell lines suggested that CCN4 repressed cell growth and simultaneously enhanced cell survival. The collective role of CCN4 suggests a potential therapeutic target for limiting metastatic invasion in melanoma and a biomarker for metastatic potential.

scholarly journals Targeting Rad51 as a strategy for the treatment of melanoma cells resistant to MAPK pathway inhibition

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Elena Makino ◽  
Lisa Marie Fröhlich ◽  
Tobias Sinnberg ◽  
Corinna Kosnopfel ◽  
Birgit Sauer ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Metastatic Melanoma ◽  
Mapk Pathway ◽  
Critical Role ◽  
Melanoma Cells ◽  
Mapk Signaling ◽  
Transcriptional Level ◽  
Mapk Inhibitor

Abstract Rad51 is an essential factor of the homologous recombination DNA repair pathway and therefore plays an important role in maintaining genomic stability. We show that RAD51 and other homologous recombination repair genes are overexpressed in metastatic melanoma cell lines and in melanoma patient samples, which correlates with reduced survival of melanoma patients. In addition, Rad51 expression in melanoma cells was regulated on a transcriptional level by the MAPK signaling pathway with Elk1 as the main downstream transcriptional effector. Most strikingly, melanoma cells which developed resistance towards MAPK inhibitors could be efficiently targeted by Rad51 inhibitors similar to their sensitive counterparts, leading to DNA damage, G2/M arrest and apoptosis. Furthermore, the treatment of MAPK inhibitor resistant cells with Rad51 inhibitors enhances the susceptibility of these cells for MAPK inhibitor treatment in vitro and in vivo. These data indicate that Rad51 plays a critical role in the survival of metastatic melanoma cells and is a promising target for the therapy of melanoma irrespective of its MAPK inhibitor resistance status.

The PI3K inhibitor BKM120 has potent antitumor activity in melanoma brain metastases in vitro and in vivo.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e20050-e20050 ◽  
Author(s):  
Friedegund Elke Meier ◽  
Heike Niessner ◽  
Jennifer Schmitz ◽  
Andreas Schmid ◽  
Carsten Calaminus ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Brain Metastases ◽  
Metastatic Melanoma ◽  
Conditioned Medium ◽  
Melanoma Cells ◽  
Pi3k Inhibitor ◽  
Survival Pathway ◽  
Melanoma Brain Metastases

e20050 Background: In melanoma, the RAF-MEK-ERK and PI3K-AKT signaling pathways play a major role in melanoma progression and drug resistance. On the basis of significant improvement in overall survival, the BRAF inhibitor vemurafenib gained FDA approval for the treatment of patients with metastatic BRAFV600E mutated melanoma. However, vemurafenib appears to be less effective in melanoma brain metastases, and brain metastases are the most common cause of death in patients with metastatic melanoma. In our previous study we reported that the AKT survival pathway is hyperactivated in melanoma brain metastases. Methods: The current study aims to investigate the mechanisms of AKT hyperactivation and the antitumor activity of the PI3K inhibitor BKM120 in melanoma brain metastases in vitro and in vivo. Results: To simulate the tumor environment of brain metastases and extracerebral metastases, brain and matched extracerebral metastatic melanoma cells were stimulated by astrocyte- and fibroblast-conditioned medium, respectively. Both brain and extracerebral metastatic melanoma cells stimulated by astrocyte-conditioned medium showed higher AKT activation and invasiveness in a transwell matrigel invasion assay than cells stimulated by fibroblast-conditioned medium. The PI3K inhibitor BKM120 inhibited the phosphorylation of AKT and the growth of >10 newly isolated cell lines derived from melanoma brain metastases achieving growth inhibition rates of up to 80%. These effects did not depend on BRAF, NRAS or KIT mutation status. Furthermore, BKM120 potently induced apoptosis in brain metastatic melanoma cells and significantly inhibited the tumor growth of human brain metastatic melanoma cells in the brain of nude mice as shown by MRI scans. Conclusions: Brain-derived factors induce hyperactivation of the AKT survival pathway and promote invasiveness and drug resistance of melanoma cells in the brain. The PI3K inhibitor BKM120 inhibits activation of the AKT survival pathway and demonstrates potent antitumor activity in melanoma brain metastases in vitro and in vivo.

scholarly journals Characterization of novel neutralizing mouse monoclonal antibody JM1-24-3 developed against MUC18 in metastatic melanoma

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Runhua Feng ◽  
Yuling Wang ◽  
Vijaya Ramachandran ◽  
Qinhong Ma ◽  
Matthew M. May ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Metastatic Melanoma ◽  
Therapeutic Target ◽  
High Throughput Screening ◽  
Conformational Epitope ◽  
Migration And Invasion ◽  
Melanoma Tumor ◽  
Downstream Signaling

Abstract Background MUC18 is a glycoprotein highly expressed on the surface of melanoma and other cancers which promotes tumor progression and metastasis. However, its mechanism of action and suitability as a therapeutic target are unknown. Methods A monoclonal antibody (mAb) (JM1-24-3) was generated from metastatic melanoma tumor live cell immunization, and high-throughput screening identified MUC18 as the target. Results Analysis of molecular interactions between MUC18 and JM1-24-3 revealed that the downstream signaling events depended on binding of the mAb to a conformational epitope on the extracellular domain of MUC18. JM1-24-3 inhibited melanoma cell proliferation, migration and invasion in vitro and reduced tumor growth and metastasis in vivo. Conclusion These results confirm that MUC18 is mechanistically important in melanoma growth and metastasis, suggest that the MUC18 epitope identified is a promising therapeutic target, and that the JM1-24-3 mAb may serve as the basis for a potential therapeutic agent.

scholarly journals Lupeol Inhibits Growth of Highly Aggressive Human Metastatic Melanoma Cells In vitro and In vivo by Inducing Apoptosis

2008 ◽  
Vol 14 (7) ◽  
pp. 2119-2127 ◽  
Author(s):  
Mohammad Saleem ◽  
Nityanand Maddodi ◽  
Mohammad Abu Zaid ◽  
Naghma Khan ◽  
Bilal bin Hafeez ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Melanoma Cells

Ancylostoma caninum Anticoagulant Peptide Blocks Metastasis In Vivo and Inhibits Factor Xa Binding to Melanoma Cells In Vitro

1998 ◽  
Vol 79 (05) ◽  
pp. 1041-1047 ◽  
Author(s):  
Kathleen M. Donnelly ◽  
Michael E. Bromberg ◽  
Aaron Milstone ◽  
Jennifer Madison McNiff ◽  
Gordon Terwilliger ◽  
...  
Keyword(s):  
Active Site ◽  
Thrombin Generation ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Melanoma Cells ◽  
Factor V ◽  
Ancylostoma Caninum ◽  
Metastatic Activity

SummaryWe evaluated the in vivo anti-metastatic activity of recombinant Ancylostoma caninum Anticoagulant Peptide (rAcAP), a potent (Ki = 265 pM) and specific active site inhibitor of human coagulation factor Xa originally isolated from bloodfeeding hookworms. Subcutaneous injection of SCID mice with rAcAP (0.01-0.2 mg/mouse) prior to tail vein injection of LOX human melanoma cells resulted in a dose dependent reduction in pulmonary metastases. In order to elucidate potential mechanisms of rAcAP’s anti-metastatic activity, experiments were carried out to identify specific interactions between factor Xa and LOX. Binding of biotinylated factor Xa to LOX monolayers was both specific and saturable (Kd = 15 nM). Competition experiments using antibodies to previously identified factor Xa binding proteins, including factor V/Va, effector cell protease receptor-1, and tissue factor pathway inhibitor failed to implicate any of these molecules as significant binding sites for Factor Xa. Functional prothrombinase activity was also supported by LOX, with a half maximal rate of thrombin generation detected at a factor Xa concentration of 2.4 nM. Additional competition experiments using an excess of either rAcAP or active site blocked factor Xa (EGR-Xa) revealed that most of the total factor Xa binding to LOX is mediated via interaction with the enzyme’s active site, predicting that the vast majority of cell-associated factor Xa does not participate directly in thrombin generation. In addition to establishing two distinct mechanisms of factor Xa binding to melanoma, these data raise the possibility that rAcAP’s antimetastatic effect in vivo might involve novel non-coagulant pathways, perhaps via inhibition of active-site mediated interactions between factor Xa and tumor cells.

Vitamin D as potential therapeutic anticancer agent

2018 ◽  
pp. 1-3
Keyword(s):  
Vitamin D ◽  
Anticancer Activity ◽  
Anticancer Agent ◽  
Antitumor Agents ◽  
Metastatic Potential ◽  
Anticancer Properties ◽  
Chemotherapy Agents

The role of vitamin D is implicated in carcinogenesis through numerous biological processes like induction of apoptosis, modulation of immune system inhibition of inflammation and cell proliferation and promotion of cell differentiation. Its use as additional adjuvant drug with cancer treatment may be novel combination for improved outcome of different cancers. Numerous preclinical, epidemiological and clinical studies support the role of vitamin D as an anticancer agent. Anticancer properties of vitamin D have been studied widely (both in vivo and in vitro) among various cancers and found to have promising results. There are considerable data that indicate synergistic potential of calcitriol and antitumor agents. Possible mechanisms for modulatory anticancer activity of vitamin D include its antiproliferative, prodifferentiating, and anti-angiogenic and apoptic properties. Calcitriol reduces invasiveness and metastatic potential of many cancer cells by inhibiting angiogenesis and regulating expression of the key molecules involved in invasion and metastasis. Anticancer activity of vitamin D is synergistic or additive with the antineoplastic actions of several drugs including cytotoxic chemotherapy agents like paclitaxel, docetaxel, platinum base compounds and mitoxantrone. Benefits of addition of vitamin D should be weighed against the risk of its toxicity.

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