Mechanosensitive ion channels push cancer progression

Pethő, Zoltán; Najder, Karolina; Bulk, Etmar; Schwab, Albrecht

doi:10.1016/j.ceca.2019.03.007

Cited by 85 publications

(80 citation statements)

References 222 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In concordance with this finding, our previous work shows that PSCs express a large amount of Piezo1 mRNA (Fels et al, 2016). Activation of Piezo1 in PSCs would lead to Ca 2+ influx which in turn prompts a myriad of cellular responses in cancer (Fels et al, 2018;Pethő et al, 2019). These responses include phosphorylation of regulatory myosin light chains (MYLs) and activation of calmodulin-dependent cellular pathways that eventually coordinate gene expression, secretion of extracellular matrix, Abbreviations: αSMA, Alpha-smooth-muscle actin; ECM, Extracellular matrix; HE, Hematoxylin-eosin stain; PDAC, Pancreatic ductal adenocarcinoma; MYL, Myosin light chain; NMIIA, Non-muscle myosin IIA; P-MYL, Phosphorylated myosin light chain; PDGF, Platelet-derived growth factor; PSC, Pancreatic stellate cell.…”

Section: Introductionsupporting

confidence: 63%

“…Ca 2+ influx will also lead to the downstream activation of calcium-activated K + channels (e.g., K Ca 3.1) which in turn feeds back on Piezo1 channels by their impact on the cell membrane potential (Storck et al, 2017;Pethő et al, 2019). In PDAC the characteristic mechanical properties of the desmoplastic microenvironment are expected to lead to continuous Piezo1 activation and hence, to sustained Ca 2+ influx.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Protonation of Piezo1 Impairs Cell-Matrix Interactions of Pancreatic Stellate Cells

et al. 2020

Self Cite

View full text Add to dashboard Cite

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an acidic and fibrotic stroma. The extracellular matrix (ECM) causing the fibrosis is primarily formed by pancreatic stellate cells (PSCs). The effects of the altered biomechanics and pH landscape in the pathogenesis of PDAC, however, are poorly understood. Mechanotransduction in cells has been linked to the function of mechanosensitive ion channels such as Piezo1. Here, we tested whether this channel plays crucial roles in transducing mechanical signals in the acidic PDAC microenvironment. We performed immunofluorescence, Ca 2+ influx and intracellular pH measurements in PSCs and complemented them by live-cell imaging migration experiments in order to assess the function of Piezo1 channels in PSCs. We evaluated whether Piezo1 responds to changes of extracellular and/or intracellular pH in the pathophysiological range (pH 6.6 and pH 6.9, respectively). We validated our results using Piezo1-transfected HEK293 cells as a model system. Indeed, acidification of the intracellular space severely inhibits Piezo1-mediated Ca 2+ influx into PSCs. In addition, stimulation of Piezo1 channels with its activator Yoda1 accelerates migration of PSCs on a two-dimensional ECM as well as in a 3D setting. Furthermore, Yoda1-activated PSCs transmit more force to the surrounding ECM under physiological pH, as revealed by measuring the dislocation of microbeads embedded in the surrounding matrix. This is paralleled by an enhanced phosphorylation of myosin light chain isoform 9 after Piezo1 stimulation. Intriguingly, upon acidification, Piezo1 activation leads to the initiation of cell death and disruption of PSC spheroids. In summary, stimulating Piezo1 activates PSCs by inducing Ca 2+ influx which in turn alters the cytoskeletal architecture. This results in increased cellular motility and ECM traction, which can be useful for the cells to invade the surroundings and to detach from the tissue. However, in the presence of an acidic extracellular pH, although net Ca 2+ influx is reduced, Piezo1 activation leads to severe cell stress also limiting cellular viability. In conclusion, our results indicate a strong interdependence between environmental pH, the mechanical output of PSCs and stromal mechanics, which promotes early local invasion of PDAC cells.

show abstract

Section: Introductionsupporting

confidence: 63%

Section: Introductionmentioning

confidence: 99%

Protonation of Piezo1 Impairs Cell-Matrix Interactions of Pancreatic Stellate Cells

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…The calcium‐activated potassium channel 3.1 (K Ca 3.1) is an intensively studied ion channel in this context. It is involved in critical steps of the metastatic cascade, such as proliferation, migration, invasion, and extravasation . Inhibition of the K Ca 3.1 channel leads in many different tumor entities to reduced proliferation, migration, and metastasis .…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Small‐Molecule Fluorescent Probes for the In Vitro Imaging of Calcium‐Activated Potassium Channel K_Ca3.1

et al. 2020

Self Cite

View full text Add to dashboard Cite

Small‐molecule probes for the in vitro imaging of KCa3.1 channel‐expressing cells were developed. Senicapoc, showing high affinity and selectivity for the KCa3.1 channels, was chosen as the targeting component. BODIPY dyes 15–20 were synthesized and connected by a CuI‐catalyzed azide–alkyne [3+2]cycloaddition with propargyl ether senicapoc derivative 8, yielding fluorescently labeled ligands 21–26. The dimethylpyrrole‐based imaging probes 25 and 26 allow staining of KCa3.1 channels in NSCLC cells. The specificity was shown by removing the punctate staining pattern by pre‐incubation with senicapoc. The density of KCa3.1 channels detected with 25 and by immunostaining was identical. The punctate structure of the labeled channels could also be observed in living cells. Molecular modeling showed binding of the senicapoc‐targeting component towards the binding site within the ion channel and orientation of the linker with the dye along the inner surface of the ion channel.

show abstract

“…It is involved in critical steps of the metastatic cascade,s uch as proliferation, migration, invasion, and extravasation. [2,3] Inhibition of the K Ca 3.1 channel leads in many different tumor entities to reduced proliferation, migration, and metastasis. [4][5][6] Overexpression of this channel directly correlates with tumor grade and metastatic status and is often related to poor prognosis for tumor patients and high lethality rates.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Small‐Molecule Fluorescent Probes for the In Vitro Imaging of Calcium‐Activated Potassium Channel K_Ca3.1

et al. 2020

Self Cite

View full text Add to dashboard Cite

Small-molecule probes for the in vitro imaging of K Ca 3.1 channel-expressing cells were developed. Senicapoc, showing high affinity and selectivity for the K Ca 3.1 channels, was chosen as the targeting component. BODIPY dyes 15-20 were synthesized and connected by aC u I -catalyzed azidealkyne [3+ +2]cycloaddition with propargyl ether senicapoc derivative 8,yielding fluorescently labeled ligands 21-26.The dimethylpyrrole-based imaging probes 25 and 26 allow staining of K Ca 3.1 channels in NSCLC cells.T he specificity was shown by removing the punctate staining pattern by preincubation with senicapoc.T he density of K Ca 3.1 channels detected with 25 and by immunostaining was identical. The punctate structure of the labeled channels could also be observed in living cells.M olecular modeling showed binding of the senicapoc-targeting component towards the binding site within the ion channel and orientation of the linker with the dye along the inner surface of the ion channel.Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.

show abstract

Mechanosensitive ion channels push cancer progression

Cited by 85 publications

References 222 publications

Protonation of Piezo1 Impairs Cell-Matrix Interactions of Pancreatic Stellate Cells

Protonation of Piezo1 Impairs Cell-Matrix Interactions of Pancreatic Stellate Cells

Synthesis of Small‐Molecule Fluorescent Probes for the In Vitro Imaging of Calcium‐Activated Potassium Channel K_Ca3.1

Synthesis of Small‐Molecule Fluorescent Probes for the In Vitro Imaging of Calcium‐Activated Potassium Channel K_Ca3.1

Contact Info

Product

Resources

About

Mechanosensitive ion channels push cancer progression

Cited by 85 publications

References 222 publications

Protonation of Piezo1 Impairs Cell-Matrix Interactions of Pancreatic Stellate Cells

Protonation of Piezo1 Impairs Cell-Matrix Interactions of Pancreatic Stellate Cells

Synthesis of Small‐Molecule Fluorescent Probes for the In Vitro Imaging of Calcium‐Activated Potassium Channel KCa3.1

Synthesis of Small‐Molecule Fluorescent Probes for the In Vitro Imaging of Calcium‐Activated Potassium Channel KCa3.1

Contact Info

Product

Resources

About

Synthesis of Small‐Molecule Fluorescent Probes for the In Vitro Imaging of Calcium‐Activated Potassium Channel K_Ca3.1

Synthesis of Small‐Molecule Fluorescent Probes for the In Vitro Imaging of Calcium‐Activated Potassium Channel K_Ca3.1