Research Papers:

KCa3.1 channel inhibition leads to an ICAM-1 dependent increase of cell-cell adhesion between A549 lung cancer and HMEC-1 endothelial cells

Etmar Bulk _, Nadzeya Kramko, Ivan Liashkovich, Felix Glaser, Hermann Schillers, Hans-Joachim Schnittler, Hans Oberleithner and Albrecht Schwab

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Oncotarget. 2017; 8:112268-112282. https://doi.org/10.18632/oncotarget.22735

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Etmar Bulk1, Nadzeya Kramko2, Ivan Liashkovich1, Felix Glaser1, Hermann Schillers1, Hans-Joachim Schnittler2, Hans Oberleithner1 and Albrecht Schwab1

1Institute of Physiology II, University of Muenster, Münster, Germany

2Institute of Anatomy and Vascular Biology, University of Muenster, Münster, Germany

Correspondence to:

Etmar Bulk, email: [email protected]

Keywords: NSCLC; extravasation; single cell force spectroscopy; KCa3.1 channels; ICAM-1

Received: July 14, 2017     Accepted: November 14, 2017     Published: November 28, 2017


Early metastasis leads to poor prognosis of lung cancer patients, whose 5-year survival rate is only 15%. We could recently show that the Ca2+ sensitive K+ channel KCa3.1 promotes aggressive behavior of non-small cell lung cancer (NSCLC) cells and that it can serve as a prognostic marker in NSCLC. Since NSCLC patients die of metastases, we investigated whether KCa3.1 channels contribute to poor patient prognosis by regulating distinct steps of the metastatic cascade. We investigated the extravasation of NSCLC cells and focused on their adhesion to endothelial cells and on transendothelial migration. We quantified the adhesion forces between NSCLC cells and endothelial cells by applying single cell force spectroscopy, and we monitored transendothelial migration using live-cell imaging. Inhibition of KCa3.1 channels with senicapoc or KCa3.1 silencing increases the adhesion force of A549 lung cancer cells to human microvascular endothelial cells (HMEC-1). Western blotting, immunofluorescence staining and biotinylation assays indicate that the elevated adhesion force is due to increased expression of ICAM-1 in both cell lines when KCa3.1 channels are downregulated. Consistent with this interpretation, an anti-ICAM-1 blocking antibody abolishes the KCa3.1-dependent increase in adhesion. Senicapoc inhibits transendothelial migration of A549 cells by 50%. Selectively silencing KCa3.1 channels in either NSCLC or endothelial cells reveals that transendothelial migration depends predominantly on endothelial KCa3.1 channels.

In conclusion, our findings disclose a novel function of KCa3.1 channels in cancer. KCa3.1 channels regulate ICAM-1 dependent cell-cell adhesion between endothelial and cancer cells that affects the transmigration step of the metastatic cascade.

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