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The SK3/K Ca 2.3 potassium channel is a new cellular target for edelfosine
Author(s) -
Potier M,
Chantome A,
Joulin V,
Girault A,
Roger S,
Besson P,
Jourdan ML,
LeGuennec JY,
Bougnoux P,
Vandier C
Publication year - 2011
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2010.01044.x
Subject(s) - apamin , chemistry , biophysics , depolarization , sk channel , potassium channel , intracellular , patch clamp , ion channel , biochemistry , biology , receptor
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 125 I‐Apamin binding experiments, we studied the effects of edelfosine on the migration of breast cancer MDA‐MB‐435s cells, mediated by the small conductance Ca 2+ ‐activated K + channel, SK3/K Ca 2.3. KEY RESULTS Edelfosine (1 µM) caused plasma membrane depolarization by substantially inhibiting activity of SK3/K Ca 2.3 channels, which we had previously demonstrated to play an important role in cancer cell migration. Edelfosine did not inhibit 125 I‐Apamin binding to this SK Ca channel; rather, it reduced the calcium sensitivity of SK3/K Ca 2.3 channel and dramatically decreased intracellular Ca 2+ concentration, probably by insertion in the plasma membrane, as suggested by proteinase K experiments. Edelfosine reduced cell migration to the same extent as known SK Ca 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/K Ca 2.3 protein in a SK3/K Ca 2.3‐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/K Ca 2.3 channels and provide insights into the future development of a new class of migration‐targeted, anti‐cancer agents.