scholarly journals The Role of Calmodulin in Tumor Cell Migration, Invasiveness, and Metastasis

2020 ◽  
Vol 21 (3) ◽  
pp. 765 ◽  
Author(s):  
Antonio Villalobo ◽  
Martin W. Berchtold
Keyword(s):  
Cell Migration ◽  
Tumor Cell ◽  
Small Gtpases ◽  
Vast Number ◽  
Mesenchymal Transition ◽  
Tumor Cell Migration ◽  
Iq Motif ◽  
Metastasis Development ◽  
Cell Invasiveness

Calmodulin (CaM) is the principal Ca2+ sensor protein in all eukaryotic cells, that upon binding to target proteins transduces signals encoded by global or subcellular-specific changes of Ca2+ concentration within the cell. The Ca2+/CaM complex as well as Ca2+-free CaM modulate the activity of a vast number of enzymes, channels, signaling, adaptor and structural proteins, and hence the functionality of implicated signaling pathways, which control multiple cellular functions. A basic and important cellular function controlled by CaM in various ways is cell motility. Here we discuss the role of CaM-dependent systems involved in cell migration, tumor cell invasiveness, and metastasis development. Emphasis is given to phosphorylation/dephosphorylation events catalyzed by myosin light-chain kinase, CaM-dependent kinase-II, as well as other CaM-dependent kinases, and the CaM-dependent phosphatase calcineurin. In addition, the role of the CaM-regulated small GTPases Rac1 and Cdc42 (cell division cycle protein 42) as well as CaM-binding adaptor/scaffold proteins such as Grb7 (growth factor receptor bound protein 7), IQGAP (IQ motif containing GTPase activating protein) and AKAP12 (A kinase anchoring protein 12) will be reviewed. CaM-regulated mechanisms in cancer cells responsible for their greater migratory capacity compared to non-malignant cells, invasion of adjacent normal tissues and their systemic dissemination will be discussed, including closely linked processes such as the epithelial–mesenchymal transition and the activation of metalloproteases. This review covers as well the role of CaM in establishing metastatic foci in distant organs. Finally, the use of CaM antagonists and other blocking techniques to downregulate CaM-dependent systems aimed at preventing cancer cell invasiveness and metastasis development will be outlined.

scholarly journals Regulators at Every Step—How microRNAs Drive Tumor Cell Invasiveness and Metastasis

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3709
Author(s):  
Tomasz M. Grzywa ◽  
Klaudia Klicka ◽  
Paweł K. Włodarski
Keyword(s):  
Cell Migration ◽  
Tumor Cell ◽  
Tumor Progression ◽  
Epithelial Mesenchymal Transition ◽  
Transcriptional Level ◽  
Invasion And Metastasis ◽  
Metastatic Niche ◽  
Mesenchymal Transition ◽  
Tumor Cell Migration ◽  
Cell Invasiveness

Tumor cell invasiveness and metastasis are the main causes of mortality in cancer. Tumor progression is composed of many steps, including primary tumor growth, local invasion, intravasation, survival in the circulation, pre-metastatic niche formation, and metastasis. All these steps are strictly controlled by microRNAs (miRNAs), small non-coding RNA that regulate gene expression at the post-transcriptional level. miRNAs can act as oncomiRs that promote tumor cell invasion and metastasis or as tumor suppressor miRNAs that inhibit tumor progression. These miRNAs regulate the actin cytoskeleton, the expression of extracellular matrix (ECM) receptors including integrins and ECM-remodeling enzymes comprising matrix metalloproteinases (MMPs), and regulate epithelial–mesenchymal transition (EMT), hence modulating cell migration and invasiveness. Moreover, miRNAs regulate angiogenesis, the formation of a pre-metastatic niche, and metastasis. Thus, miRNAs are biomarkers of metastases as well as promising targets of therapy. In this review, we comprehensively describe the role of various miRNAs in tumor cell migration, invasion, and metastasis.

A Truncated Snail1 Transcription Factor Alters the Expression of Essential EMT Markers and Suppresses Tumor Cell Migration in a Human Lung Cancer Cell Line

2019 ◽  
Vol 14 (2) ◽  
pp. 158-169 ◽  
Author(s):  
Mohammad Davoodzadeh Gholami ◽  
Reza Falak ◽  
Sahel Heidari ◽  
Majid Khoshmirsafa ◽  
Mohammad H. Kazemi ◽  
...  
Keyword(s):  
Cell Migration ◽  
Tumor Cell ◽  
Cancer Metastasis ◽  
A549 Cells ◽  
Human Lung Cancer ◽  
Mesenchymal Transition ◽  
Tumor Cell Migration ◽  
E Box ◽  
Emt Markers ◽  
Tgf Β1

Background: Epithelial-to-Mesenchymal Transition (EMT) is necessary for metastasis. Zinc- finger domain-containing transcription factors, especially Snail1, bind to E-box motifs and play a crucial role in the induction and regulation of EMT. Objective: We hypothesized if C-terminal region of Snail1 (CSnail1) may competitively bind to E-box and block cancer metastasis. Methods: The CSnail1 gene coding sequence was inserted into the pIRES2-EGFP vector. Following transfection of A549 cells with the designed construct, EMT was induced with TGF-β1 and the expression of essential EMT markers was evaluated by real-time PCR and immunoblotting. We also monitored cell migration. Results: CSnail1 inhibited TGF-β1-induced N-cadherin and vimentin mRNA expression and increased β-catenin expression in transfected TGF-β1-treated A549 cells. A similar finding was obtained in western blotting. CSnail1 also blocked the migration of transfected cells in the scratch test. Conclusions: Transfection of A549 cells with CSnail1 alters the expression of essential EMT markers and consequently suppresses tumor cell migration. These findings confirm the capability of CSnail1 in EMT blocking and in parallel to current patents could be applied as a novel strategy in the prevention of metastasis.

scholarly journals Neutrophil Granulocytes in Ovarian Cancer - Induction of Epithelial-To-Mesenchymal-Transition and Tumor Cell Migration

2016 ◽  
Vol 7 (5) ◽  
pp. 546-554 ◽  
Author(s):  
Christine Mayer ◽  
Silvia Darb-Esfahani ◽  
Anne-Sophie Meyer ◽  
Katrin Hübner ◽  
Joachim Rom ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Migration ◽  
Tumor Cell ◽  
Epithelial To Mesenchymal Transition ◽  
Neutrophil Granulocytes ◽  
Mesenchymal Transition ◽  
Tumor Cell Migration ◽  
Cancer Induction

The Cytoplasmic Domain of Tissue Factor Inhibits Migration and Enhances Adhesion of Human Breast Cancer Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1939-1939
Author(s):  
Xiaofeng Jiang ◽  
Tracee S. Panetti ◽  
Michael E. Bromberg
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Tumor Cell ◽  
Cell Line ◽  
Human Breast Cancer ◽  
Cytoplasmic Domain ◽  
Human Breast ◽  
Tumor Cell Migration ◽  
Mcf 7

Abstract Tissue factor (TF) is a 47 kDa transmembrane glycoprotein that when complexed with its cofactor, factor VIIa (FVIIa), initiates blood coagulation. Apart from hemostasis, TF has been shown to have roles in cellular signaling, development, inflammation, metastasis and angiogenesis. We showed previously that both the cytoplasmic and extracellular domains of TF are required for the full metastatic effect of TF. Recently, we showed that TF-FVIIa-FXa complex induces cellular signaling in human breast cancer cells and is associated with enhanced cell migration and prevention of apoptosis. However, the role of the cytoplasmic domain of TF in tumor cell function is not fully known. In the present study, the role of the cytoplasmic domain of TF in cell migration and adhesion was investigated using the Adr-MCF-7 cell line, a multidrug resistant subline of the human breast cancer cell line, MCF-7. The Adr-MCF-7 cell line has high endogenous expression of TF and expression of PAR1 and PAR2. Adr-MCF-7 cells were retrovirally transfected with either a cDNA construct encoding a FLAG epitope tag fused to the transmembrane and cytoplasmic domains of TF (known as FLAG-TFCD) or vector (LXSN) alone as a control, and stable, polyclonal cell lines selected using G418. Expression of the FLAG-TFCD construct was verified by RT-PCR, Western blot analysis and flow cytometry. To test the effect of overexpression of the FLAG-TFCD construct on cell motility a modified Boyden chamber chemotaxis assay was used. The control LXSN cell line had a nearly 9 fold increase in cell migration [33.5± 3.2 cells/hpf (mean± SEM)]using the combination of rFVIIa (10 nM) and FX (150 nM) as the chemoattractant compared with 0.1% bovine serum albumin (BSA) [3.9± 1.2 cells/hpf]. In contrast, the FLAG-TFCD cell line had no increase in migration of using the combination of rFVIIa and FX [6.6± 0.57 cells/hpf] compared with BSA [5.4± 0.67 cells/hpf]. We then examined the ability of the transfected cell lines to adhere to type IV collagen. The number of adherent cells for the transfected cell line, FLAG-TFCD, was nearly 3 fold higher than that for the LXSN line using a colorimetric MTS assay (0.295± 0.041 vs 0.119± 0.011). Moreover, treatment of the FLAG-TFCD cells with the combination of rFVIIa and FX increased the adhesion by nearly 2 fold compared with untreated FLAG-TFCD cells (0.561±0.055 vs 0.296±0.044). In summary, overexpression of TF cytoplasmic domain leads to inhibition of tumor cell migration and enhancement of cell adhesion and potentially acts as a dominant negative in these cellular processes. These data suggest that a function of the cytoplasmic domain of TF in metastasis is to regulate tumor cell migration and adhesion.

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