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

Maxime Guéguinou 1, 2 Thomas Harnois 3, 1 David Crottes 4 Arnaud Uguen 5, 6 Nadine Deliot 3, 1 Audrey Gambade 2 Aurélie Chantôme 2, 1 Jean Pierre Haelters 7, 1 Paul-Alain Jaffres 7 Marie Lise Jourdan 2, 8 Gunther Weber 2 Olivier Soriani 9 Philippe Bougnoux 2, 8, 1 Olivier Mignen 2, 1 Nicolas Bourmeyster 3, 1 Thierry Lecomte 10, 8, 1 Bruno Constantin 3, 1 Christophe Vandier 2, 1 Marie Potier-Cartereau 2, 1
1 Network “Ion channels and Cancer-Canceropole Grand Ouest”
2 N2C - Nutrition, croissance et cancer (U 1069)
3 STIM - Signalisation et Transports Ioniques Membranaires
4 UCSF - University of California [San Francisco]
5 Génétique, génomique fonctionnelle et biotechnologies (UMR 1078)
6 Service d’Anatomie et Cytologie Pathologiques
7 CEMCA - Chimie, Electrochimie Moléculaires et Chimie Analytique
8 CHU Trousseau [Tours]
9 CNRS UMR 7299, INSERM-UMR 1099
10 GICC - Génétique, Immunothérapie, Chimie et Cancer
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.
Keywords : SOCE Ohmline lipid-raft channel complex anti-EGFR mAbs Akt signaling
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Contributeur : Nicolas Renard <>
Soumis le : jeudi 15 juin 2017 - 10:01:38
Dernière modification le : jeudi 13 septembre 2018 - 16:37:10

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Maxime Guéguinou, Thomas Harnois, David Crottes, Arnaud Uguen, Nadine Deliot, et al.. 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. Oncotarget, Impact journals, 2016, 〈http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path=8786&path=26521〉. 〈10.18632/oncotarget.8786〉. 〈hal-01539569〉

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