scholarly journals The glycolysis regulator PFKFB4 interacts with ICMT and activates RAS/AKT signaling-dependent cell migration in melanoma

2020 ◽  
Author(s):  
Méghane Sittewelle ◽  
Déborah Lécuyer ◽  
Anne H. Monsoro-Burq
Keyword(s):  
Plasma Membrane ◽  
Cell Migration ◽  
Melanoma Cell ◽  
Protein Interactions ◽  
Cancer Metastasis ◽  
Human Cancer ◽  
Akt Signaling ◽  
List Type ◽  
Cell Parameters ◽  
Cancer Hallmarks

AbstractCell migration is a complex process, tightly regulated during embryonic development and abnormally activated during cancer metastasis. RAS-dependent signaling is a major nexus controlling essential cell parameters such as proliferation, survival and migration using downstream effectors among which the PI3K/AKT signaling. In melanoma, oncogenic mutations frequently enhance RAS, PI3K/AKT or MAP kinase signaling, in addition to other cancer hallmarks including the activation of metabolism regulators such as PFKFB4, a critical regulator of glycolysis and Warburg effect. Here, we explore a novel function of PFKFB4 in melanoma cell migration. We find that instead of acting as a kinase as recorded in glycolysis, PFKFB4 interacts with ICMT, a post-translational modifier of RAS. PFKFB4 promotes ICMT/RAS interaction, controls RAS addressing at the plasma membrane, activates AKT signaling and enhances cell migration. We thus evidence a novel glycolysis-independent function of PFKFB4 in human cancer cells. This unconventional activity links the metabolic regulator PFKFB4 to RAS-AKT signaling and impacts melanoma cell migration.Highlights- PFKFB4, a known regulator of glycolysis, displays an unconventional role in melanoma cell migration.- PFKFB4 interacts with ICMT by protein-protein interactions and promotes RAS addressing at the plasma membrane.- PFKFB4 and ICMT cooperation modulates AKT signaling and controls melanoma cell migration.

scholarly journals Perturbation of BRMS1 interactome reveals pathways that impact cell migration

2021 ◽  
Author(s):  
Rosalyn Zimmermann ◽  
Mihaela E. Sardiu ◽  
Christa A. Manton ◽  
Md. Sayem Miah ◽  
Charles A.S. Banks ◽  
...  
Keyword(s):  
Cell Migration ◽  
Protein Interactions ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Metastasis Suppressor ◽  
Protein Protein Interactions ◽  
Multiple Cancer ◽  
C Terminus ◽  
Metastasis Suppression

AbstractBreast Cancer Metastasis Suppressor 1 (BRMS1) expression has been associated with longer patient survival in multiple cancer types. Understanding BRMS1 at the protein level will provide insights into both mechanism of action and enhance potential therapeutic development. We previously mapped the C-terminus of BRMS1 as critical for metastasis suppression and hypothesized that critical protein interactions in this region will explain function. These studies indicate that phosphorylation status at S237 regulates BRMS1 interactions related to a variety of biological processes, phenotypes [cell cycle (e.g., CDKN2A), DNA repair (e.g., BRCA1)], and metastasis [(e.g., TCF2 and POLE2)]. Presence of the C-terminal site appears to be critical for BRMS1 directed metastasis suppression, as demonstrated by in vitro migration assays. These assays demonstrated that presence of S237 directly decreased MDA-MB-231 migration. This study furthers our understanding of BRMS1’s molecular role, as it demonstrates that BRMS1 C-terminus is involved in direct protein-protein interactions. Several of the interacting proteins are associated with cancer and metastasis, which may result in metastasis suppression as suggested by in vitro findings.Abstract FigureGraphical AbstractUtilizing BRMS1 mutants to mimic-phosphorylation, this study demonstrates that S237-phosphorylation disrupts BRMS1 protein-protein interactions. The disruption includes both known Sin3/HDAC interactors as well as additionally previously unidentified Sin3-indepedent binding partners (indicated by increased opacity). It is revealed that BRMS1-phosphorylation status also more greatly inhibits cell migration (indicated by +) compared to the unphosphorylated state, suggesting that phosphorylation plays a role in BRMS1 metastatsis suppresion function, potentially though altered protein interactions.

scholarly journals Disentangling cadherin-mediated cell-cell interactions in collective cancer cell migration

2021 ◽  
Author(s):  
Themistoklis Zisis ◽  
David B. Brückner ◽  
Tom Brandstätter ◽  
Joseph d'Alessandro ◽  
Angelika M. Vollmar ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cancer Metastasis ◽  
Human Cancer ◽  
Human Cancer Cells ◽  
Cell Dispersion ◽  
Intercellular Contacts ◽  
Quantitative Understanding ◽  
Average Spreading ◽  
Colony Spreading

Cell dispersion from a confined area is fundamental in a number of biological processes, including cancer metastasis. To date, a quantitative understanding of the interplay of single cell motility, cell proliferation, and intercellular contacts remains elusive. In particular, the role of E- and N-Cadherin junctions, central components of intercellular contacts, is still controversial. Combining theoretical modeling with in vitro observations, we investigate the collective spreading behavior of colonies of human cancer cells (T24). Inhibition of E- and N-Cadherin junctions decreases colony spreading and average spreading velocities, without affecting the strength of correlations in spreading velocities of neighboring cells. Based on a biophysical simulation model for cell migration, we show that the behavioral changes upon disruption of these junctions can be explained by reduced repulsive excluded volume interactions between cells. This suggests that cadherin-based intercellular contacts sharpen cell boundaries leading to repulsive rather than cohesive interactions between cells, thereby promoting efficient cell spreading during collective migration.

scholarly journals Fascin in Cell Migration: More Than an Actin Bundling Protein

Biology ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 403
Author(s):  
Maureen C. Lamb ◽  
Tina L. Tootle
Keyword(s):  
Cell Migration ◽  
Protein Interactions ◽  
Cancer Metastasis ◽  
Control Cell ◽  
Actin Binding ◽  
Linc Complex ◽  
Protein Protein Interactions ◽  
Post Translational Modifications ◽  
Promote Cell Migration ◽  
The Many

Fascin, an actin-binding protein, regulates many developmental migrations and contributes to cancer metastasis. Specifically, Fascin promotes cell motility, invasion, and adhesion by forming filopodia and invadopodia through its canonical actin bundling function. In addition to bundling actin, Fascin has non-canonical roles in the cell that are thought to promote cell migration. These non-canonical functions include regulating the activity of other actin-binding proteins, binding to and regulating microtubules, mediating mechanotransduction to the nucleus via interaction with the Linker of the Nucleoskeleton and Cytoskeleton (LINC) Complex, and localizing to the nucleus to regulate nuclear actin, the nucleolus, and chromatin modifications. The many functions of Fascin must be coordinately regulated to control cell migration. While much remains to be learned about such mechanisms, Fascin is regulated by post-translational modifications, prostaglandin signaling, protein–protein interactions, and transcriptional means. Here, we review the structure of Fascin, the various functions of Fascin and how they contribute to cell migration, the mechanisms regulating Fascin, and how Fascin contributes to diseases, specifically cancer metastasis.

scholarly journals Plasma Membrane Ca2+ ATPase Isoform 4 (PMCA4) Has an Important Role in Numerous Hallmarks of Pancreatic Cancer

Cancers ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 218 ◽  
Author(s):  
Pishyaporn Sritangos ◽  
Eduardo Pena Alarcon ◽  
Andrew D. James ◽  
Ahlam Sultan ◽  
Daniel A. Richardson ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Cell Migration ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Patient Survival ◽  
Ductal Adenocarcinoma ◽  
Plasma Membrane Calcium Atpase ◽  
Cancer Hallmarks ◽  
Poor Patient ◽  
Resistance Data ◽  
Poor Patient Survival

Pancreatic ductal adenocarcinoma (PDAC) is largely resistant to standard treatments leading to poor patient survival. The expression of plasma membrane calcium ATPase-4 (PMCA4) is reported to modulate key cancer hallmarks including cell migration, growth, and apoptotic resistance. Data-mining revealed that PMCA4 was over-expressed in pancreatic ductal adenocarcinoma (PDAC) tumors which correlated with poor patient survival. Western blot and RT-qPCR revealed that MIA PaCa-2 cells almost exclusively express PMCA4 making these a suitable cellular model of PDAC with poor patient survival. Knockdown of PMCA4 in MIA PaCa-2 cells (using siRNA) reduced cytosolic Ca2+ ([Ca2+]i) clearance, cell migration, and sensitized cells to apoptosis, without affecting cell growth. Knocking down PMCA4 had minimal effects on numerous metabolic parameters (as assessed using the Seahorse XF analyzer). In summary, this study provides the first evidence that PMCA4 is over-expressed in PDAC and plays a role in cell migration and apoptotic resistance in MIA PaCa-2 cells. This suggests that PMCA4 may offer an attractive novel therapeutic target in PDAC.

scholarly journals The Plasma Membrane Ca2+ Pump PMCA4b Regulates Melanoma Cell Migration Through Remodeling of the Actin Cytoskeleton

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1354
Author(s):  
Randa Naffa ◽  
Rita Padányi ◽  
Attila Ignácz ◽  
Zoltán Hegyi ◽  
Bálint Jezsó ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Cell Migration ◽  
Actin Cytoskeleton ◽  
Melanoma Cell ◽  
Critical Role ◽  
Melanoma Cells ◽  
Fiber Formation ◽  
Actin Dynamics ◽  
Cell Phenotype ◽  
Braf Mutant

We demonstrated that the plasma membrane Ca2+ ATPase PMCA4b inhibits migration and metastatic activity of BRAF mutant melanoma cells. Actin dynamics are essential for cells to move, invade and metastasize, therefore, we hypothesized that PMCA4b affected cell migration through remodeling of the actin cytoskeleton. We found that expression of PMCA4b in A375 BRAF mutant melanoma cells induced a profound change in cell shape, cell culture morphology, and displayed a polarized migratory character. Along with these changes the cells became more rounded with increased cell–cell connections, lamellipodia and stress fiber formation. Silencing PMCA4b in MCF-7 breast cancer cells had a similar effect, resulting in a dramatic loss of stress fibers. In addition, the PMCA4b expressing A375 cells maintained front-to-rear Ca2+ concentration gradient with the actin severing protein cofilin localizing to the lamellipodia, and preserved the integrity of the actin cytoskeleton from a destructive Ca2+ overload. We showed that both PMCA4b activity and trafficking were essential for the observed morphology and motility changes. In conclusion, our data suggest that PMCA4b plays a critical role in adopting front-to-rear polarity in a normally spindle-shaped cell type through F-actin rearrangement resulting in a less aggressive melanoma cell phenotype.

scholarly journals Connexin43 controls N-cadherin transcription during collective cell migration

2017 ◽  
Author(s):  
Maria Kotini ◽  
Elias H. Barriga ◽  
Jonathan Leslie ◽  
Marc Gentzel ◽  
Alexandra Schambony ◽  
...  
Keyword(s):  
Cell Migration ◽  
Gap Junctions ◽  
Neural Crest ◽  
Cancer Metastasis ◽  
Embryonic Cell ◽  
Collective Cell Migration ◽  
List Type ◽  
Cellular Processes ◽  
Physiological Processes

AbstractConnexins are the primary components of gap junctions, providing direct links between cells in many physiological processes, including cell migration and cancer metastasis. Exactly how cell migration is controlled by gap junctions remains a mystery. To shed light on this, we investigated the role of Connexin43 in collective cell migration during embryo development using the neural crest, an embryonic cell population whose migratory behavior has been likened to cancer invasion. We discovered that Connexin43 is required for contact inhibition of locomotion by directly regulating the transcription of N-cadherin. For this function, the Connexin43 carboxy tail interacts with Basic Transcription Factor 3, which mediates its translocation to the nucleus. Together, they bind to the n-cad promotor regulating n-cad transcription. Thus, we uncover an unexpected, gap junction-independent role for Connexin43 in collective migration that illustrates the possibility that connexins, in general, may be important for a wide variety of cellular processes that we are only beginning to understand.HighlightsCx43 regulates collective directional migration of neural crest cellsCx43 carboxy tail controls cell polarity via n-cad regulationCx43 carboxy tail localises at the nucleus and that depends on BTF3BTF3 and Cx43 carboxy tail directly interact to bind and regulate n-cad promoter activity

scholarly journals Erianthridin suppresses non-small-cell lung cancer cell metastasis through inhibition of Akt/mTOR/p70S6K signaling pathway

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sutthaorn Pothongsrisit ◽  
Kuntarat Arunrungvichian ◽  
Yoshihiro Hayakawa ◽  
Boonchoo Sritularak ◽  
Supachoke Mangmool ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Migration ◽  
Protein Kinase ◽  
Small Cell Lung Cancer ◽  
Cancer Metastasis ◽  
Small Cell ◽  
Migration And Invasion ◽  
Lung Cancer Cell ◽  
Small Cell Lung ◽  
Cell Metastasis

AbstractCancer metastasis is a major cause of the high mortality rate in lung cancer patients. The cytoskeletal rearrangement and degradation of extracellular matrix are required to facilitate cell migration and invasion and the suppression of these behaviors is an intriguing approach to minimize cancer metastasis. Even though Erianthridin (ETD), a phenolic compound isolated from the Thai orchid Dendrobium formosum exhibits various biological activities, the molecular mechanism of ETD for anti-cancer activity is unclear. In this study, we found that noncytotoxic concentrations of ETD (≤ 50 μM) were able to significantly inhibit cell migration and invasion via disruption of actin stress fibers and lamellipodia formation. The expression of matrix metalloproteinase-2 (MMP-2) and MMP-9 was markedly downregulated in a dose-dependent manner after ETD treatment. Mechanistic studies revealed that protein kinase B (Akt) and its downstream effectors mammalian target of rapamycin (mTOR) and p70 S6 kinase (p70S6K) were strongly attenuated. An in silico study further demonstrated that ETD binds to the protein kinase domain of Akt with both hydrogen bonding and van der Waals interactions. In addition, an in vivo tail vein injection metastasis study demonstrated a significant effect of ETD on the suppression of lung cancer cell metastasis. This study provides preclinical information regarding ETD, which exhibits promising antimetastatic activity against non-small-cell lung cancer through Akt/mTOR/p70S6K-induced actin reorganization and MMPs expression.

scholarly journals Ovalitenone Inhibits the Migration of Lung Cancer Cells via the Suppression of AKT/mTOR and Epithelial-to-Mesenchymal Transition

Molecules ◽  
2021 ◽  
Vol 26 (3) ◽  
pp. 638
Author(s):  
Kittipong Sanookpan ◽  
Nongyao Nonpanya ◽  
Boonchoo Sritularak ◽  
Pithi Chanvorachote
Keyword(s):  
Lung Cancer ◽  
Cell Migration ◽  
Cancer Cells ◽  
Colony Formation ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
A549 Cells ◽  
Lung Cancer Cells ◽  
Migration And Invasion ◽  
Mesenchymal Transition

Cancer metastasis is the major cause of about 90% of cancer deaths. As epithelial-to-mesenchymal transition (EMT) is known for potentiating metastasis, this study aimed to elucidate the effect of ovalitenone on the suppression of EMT and metastasis-related behaviors, including cell movement and growth under detached conditions, and cancer stem cells (CSCs), of lung cancer cells. Methods: Cell viability and cell proliferation were determined by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazo-liumbromide (MTT) and colony formation assays. Cell migration and invasion were analyzed using a wound-healing assay and Boyden chamber assay, respectively. Anchorage-independent cell growth was determined. Cell protrusions (filopodia) were detected by phalloidin-rhodamine staining. Cancer stem cell phenotypes were assessed by spheroid formation. The proteins involved in cell migration and EMT were evaluated by Western blot analysis and immunofluorescence staining. Results: Ovalitenone was used at concentrations of 0–200 μM. While it caused no cytotoxic effects on lung cancer H460 and A549 cells, ovalitenone significantly suppressed anchorage-independent growth, CSC-like phenotypes, colony formation, and the ability of the cancer to migrate and invade cells. The anti-migration activity was confirmed by the reduction of filopodia in the cells treated with ovalitenone. Interestingly, we found that ovalitenone could significantly decrease the levels of N-cadherin, snail, and slug, while it increased E-cadherin, indicating EMT suppression. Additionally, the regulatory signaling of focal adhesion kinase (FAK), ATP-dependent tyrosine kinase (AKT), the mammalian target of rapamycin (mTOR), and cell division cycle 42 (Cdc42) was suppressed by ovalitenone. Conclusions: The results suggest that ovalitenone suppresses EMT via suppression of the AKT/mTOR signaling pathway. In addition, ovalitenone exhibited potential for the suppression of CSC phenotypes. These data reveal the anti-metastasis potential of the compound and support the development of ovalitenone treatment for lung cancer therapy.

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