The SK3/K<sub>Ca</sub>2.3 potassium channel is a new cellular target for edelfosine

British Journal of Pharmacology - Tập 162 Số 2 - Trang 464-479 - 2011
Marie‐Claude Potier1, A Chantome1, V. Joulin2, Alban Girault1, Sébastien Roger1, Pierre Besson1, Michel Jourdan1, Jean-Yves Leguennec1,3, Philippe Bougnoux1, Christophe Vandier1
1Inserm, U921, Université François Rabelais, Tours, France
2CNRS, FRE 2939, Institut Gustave Roussy, Villejuif, France
3Present address: Inserm U637 Physiopathologie Cardiovasculaire, Université Montpellier-2, 34295 Montpellier, France.

Tóm tắt

BACKGROUND AND PURPOSE The 1‐O‐octadecyl‐2‐O‐methyl‐sn‐glycero‐3‐phosphocholine (edelfosine) is an ether‐linked phospholipid with promising anti‐cancer properties but some side effects that preclude its full clinical therapeutic exploitation. We hypothesized that this lipid could interact with plasma membrane ion channels and modulate their function.EXPERIMENTAL APPROACH Using cell migration‐proliferation assays, patch clamp, spectrofluorimetry and 125I‐Apamin binding experiments, we studied the effects of edelfosine on the migration of breast cancer MDA‐MB‐435s cells, mediated by the small conductance Ca2+‐activated K+ channel, SK3/KCa2.3.KEY RESULTS Edelfosine (1 µM) caused plasma membrane depolarization by substantially inhibiting activity of SK3/KCa2.3 channels, which we had previously demonstrated to play an important role in cancer cell migration. Edelfosine did not inhibit 125I‐Apamin binding to this SKCa channel; rather, it reduced the calcium sensitivity of SK3/KCa2.3 channel and dramatically decreased intracellular Ca2+ concentration, probably by insertion in the plasma membrane, as suggested by proteinase K experiments. Edelfosine reduced cell migration to the same extent as known SKCa channel blockers. In contrast, K+ channel openers prevented edelfosine‐induced anti‐migratory effects. SK3 protein knockdown decreased cell migration and totally abolished the effect of edelfosine on MDA‐MB‐435s cell migration. In contrast, transient expression of SK3/KCa2.3 protein in a SK3/KCa2.3‐deficient cell line increased cell migration and made these cells responsive to edelfosine.CONCLUSIONS AND IMPLICATIONS Our data clearly establish edelfosine as an inhibitor of cancer cell migration by acting on SK3/KCa2.3 channels and provide insights into the future development of a new class of migration‐targeted, anti‐cancer agents.

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British Journal of Pharmacology

Tập 162 Số 2

464-479

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