Activation of TRPV2 and BKCa channels by the LL-37 enantiomers stimulates calcium entry and migration of cancer cells

// Audrey Gambade 1, * , Sami Zreika 2, * , Maxime Guéguinou 1, 3 , Igor Chourpa 4 , Gaëlle Fromont 1, 3, 5 , Ana Maria Bouchet 1, 3 , Julien Burlaud-Gaillard 4 , Marie Potier-Cartereau 1, 3 , Sébastien Roger 1 , Vincent Aucagne 6 , Stéphan Chevalier 1 , Christophe Vandier 1, 3 , Caroline Goupille 1, 5, * , Günther Weber 1, 4, * 1 Inserm, UMR1069, Nutrition, Croissance et Cancer, Tours, France 2 Department of Medical Lab Technology, Jinan University, Tripoli, Lebanon 3 Ion channel network Canceropole Grand Ouest 4 Université François Rabelais, Tours, France 5 CHRU Hôpital Bretonneau, Tours, France 6 Centre de Biophysique Moléculaire, CNRS UPR 4301, Orléans, France * These authors are contributed equally to this work Correspondence to: Günther Weber, e-mail: gunther.weber@univ-tours.fr Keywords: LL-37, calcium signaling, membrane association, cell migration, breast cancer Received: December 16, 2015      Accepted: February 28, 2016      Published: March 16, 2016 ABSTRACT Expression of the antimicrobial peptide hCAP18/LL-37 is associated to malignancy in various cancer forms, stimulating cell migration and metastasis. We report that LL-37 induces migration of three cancer cell lines by activating the TRPV2 calcium-permeable channel and recruiting it to pseudopodia through activation of the PI3K/AKT pathway. Ca 2+ entry through TRPV2 cooperated with a K + efflux through the BKCa channel. In a panel of human breast tumors, the expression of TRPV2 and LL-37 was found to be positively correlated. The D-enantiomer of LL-37 showed identical effects as the L-peptide, suggesting that no binding to a specific receptor was involved. LL-37 attached to caveolae and pseudopodia membranes and decreased membrane fluidity, suggesting that a modification of the physical properties of the lipid membrane bilayer was the underlying mechanism of its effects.