Activation of TRPV2 and BKCa channels by the LL-37 enantiomers stimulates calcium entry and migration of cancer cells
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Audrey Gambade1,*, Sami Zreika2,*, Maxime Guéguinou1,3, Igor Chourpa4, Gaëlle Fromont1,3,5, Ana Maria Bouchet1,3, Julien Burlaud-Gaillard4, Marie Potier-Cartereau1,3, Sébastien Roger1, Vincent Aucagne6, Stéphan Chevalier1, Christophe Vandier1,3, Caroline Goupille1,5,*, Günther Weber1,4,*
1Inserm, UMR1069, Nutrition, Croissance et Cancer, Tours, France
2Department of Medical Lab Technology, Jinan University, Tripoli, Lebanon
3Ion channel network Canceropole Grand Ouest
4Université François Rabelais, Tours, France
5CHRU Hôpital Bretonneau, Tours, France
6Centre de Biophysique Moléculaire, CNRS UPR 4301, Orléans, France
*These authors are contributed equally to this work
Günther Weber, e-mail: firstname.lastname@example.org
Keywords: LL-37, calcium signaling, membrane association, cell migration, breast cancer
Received: December 16, 2015 Accepted: February 28, 2016 Published: March 16, 2016
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. Ca2+ 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.
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