Endogenous ether-lipids differentially promote tumour aggressiveness by regulating the SK3 channel

Abstract

SK3 channels are potassium channels found to promote tumour aggressiveness. We have previously demonstrated that SK3 is regulated by synthetic ether-lipids, but the role of endogenous ether lipids is unknown. Here, we have studied the role of endogenous alkyl- and alkenyl-ether-lipids on SK3 channels and on the biology of cancer cells. Experiments revealed that the suppression of AGPS or PEDS1, which are key enzymes for alkyl- and alkenyl-ether-lipid synthesis, respectively, decreased SK3 expression by increasing miR-499 and miR-208 expression, leading to a decrease in SK3-dependent calcium entry, cell migration, and MMP9-dependent cell adhesion and invasion. We identified several ether-lipids that promoted SK3 expression and found a differential role of alkyl- and alkenyl-ether-lipids on SK3 activity. The expressions of AGPS, SK3, and miR were associated in clinical samples emphasising the clinical consistency of our observations. To our knowledge, this is the first report showing that ether-lipids differentially control tumour aggressiveness by regulating an ion channel. This insight provides new possibilities for therapeutic interventions, offering clinicians an opportunity to manipulate ion channel dysfunction by adjusting the composition of ether-lipids.

Keywords: SK3 channel; ether lipids; miRNA; potassium channels.