SK3/TRPC1/Orai1 complex regulates SOCE-dependent colon cancer cell migration: a novel opportunity to modulate anti-EGFR mAb action by the alkyl-lipid Ohmline

Abstract

// Maxime Guéguinou 1, 9 , Thomas Harnois 2, 9 , David Crottes 3 , Arnaud Uguen 6, 7 , Nadine Deliot 2, 9 , Audrey Gambade 1 , Aurélie Chantôme 1, 9 , Jean Pierre Haelters 4, 9 , Paul Alain Jaffrès 4, 9 , Marie Lise Jourdan 1, 10 , Günther Weber 1 , Olivier Soriani 8 , Philippe Bougnoux 1, 9, 10 , Olivier Mignen 6, 9 , Nicolas Bourmeyster 2, 9 , Bruno Constantin 2, 9 , Thierry Lecomte 5, 9, 10 , Christophe Vandier 1, 9, * , Marie Potier-Cartereau 1, 9, * 1 INSERM UMR 1069, Université de Tours, Tours, France 2 Equipe ERL 7368, CNRS, Université de Poitiers, Poitiers, France 3 Department of Physiology, University of California, San Francisco, San Francisco, CA, USA 4 CNRS-UMR 6521-Université de Brest, Brest, France 5 GICC-UMR 7292 Université de Tours, Tours, France 6 INSERM-UMR 1078 Université de Brest, Brest, France 7 CHRU Brest, Service d’Anatomie et Cytologie Pathologiques, Brest, France 8 CNRS UMR 7299, INSERM-UMR 1099, Université de Nice Sophia-Antipolis, Nice, France 9 Ion Channels Network and Cancer-Cancéropôle Grand Ouest (IC-CGO), France 10 CHRU Tours, Tours, France * These authors have contributed equally to this work Correspondence to: Marie Potier-Cartereau, email: marie.potier-cartereau@univ-tours.fr Keywords: SOCE, Ohmline, lipid-raft channel complex, anti-EGFR mAbs, Akt signaling Received: September 24, 2015      Accepted: March 28, 2016      Published: April 18, 2016 ABSTRACT Background: Barely 10-20% of patients with metastatic colorectal cancer (mCRC) receive a clinical benefit from the use of anti-EGFR monoclonal antibodies (mAbs). We hypothesized that this could depends on their efficiency to reduce Store Operated Calcium Entry (SOCE) that are known to enhance cancer cells. Results: In the present study, we demonstrate that SOCE promotes migration of colon cancer cell following the formation of a lipid raft ion channel complex composed of TRPC1/Orai1 and SK3 channels. Formation of this complex is stimulated by the phosphorylation of the reticular protein STIM1 by EGF and activation of the Akt pathway. Our data show that, in a positive feedback loop SOCE activates both Akt pathway and SK3 channel activity which lead to SOCE amplification. This amplification occurs through the activation of Rac1/Calpain mediated by Akt. We also show that Anti-EGFR mAbs can modulate SOCE and cancer cell migration through the Akt pathway. Interestingly, the alkyl-lipid Ohmline, which we previously showed to be an inhibitor of SK3 channel, can dissociated the lipid raft ion channel complex through decreased phosphorylation of Akt and modulation of mAbs action. Conclusions: This study demonstrates that the inhibition of the SOCE-dependent colon cancer cell migration trough SK3/TRPC1/Orai1 channel complex by the alkyl-lipid Ohmline may be a novel strategy to modulate Anti-EGFR mAb action in mCRC.