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The SigmaR1 chaperone drives breast and colorectal cancer cell migration by tuning SK3-dependent Ca2+ homeostasis

Oncogene volume 36, pages 3640–3647 (2017)Cite this article

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Abstract

The remodeling of calcium homeostasis contributes to the cancer hallmarks and the molecular mechanisms involved in calcium channel regulation in tumors remain to be characterized. Here, we report that SigmaR1, a stress-activated chaperone, is required to increase calcium influx by triggering the coupling between SK3, a Ca2+-activated K+ channel (KCNN3) and the voltage-independent calcium channel Orai1. We show that SigmaR1 physically binds SK3 in BC cells. Inhibition of SigmaR1 activity, either by molecular silencing or by the use of sigma ligand (igmesine), decreased SK3 current and Ca2+ entry in breast cancer (BC) and colorectal cancer (CRC) cells. Interestingly, SigmaR1 inhibition diminished SK3 and/or Orai1 levels in lipid nanodomains isolated from BC cells. Analyses of tissue microarray from CRC patients showed higher SigmaR1 expression levels in cancer samples and a correlation with tumor grade. Moreover, the exploration of a cohort of 4937 BC patients indicated that high expression of SigmaR1 and Orai1 channels was significantly correlated to a lower overall survival. As the SK3/Orai1 tandem drives invasive process in CRC and bone metastasis progression in BC, our results may inaugurate innovative therapeutic approaches targeting SigmaR1 to control the remodeling of Ca2+ homeostasis in epithelial cancers.

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Acknowledgements

The study was supported by Université Côte d'Azur, CNRS, La Ligue contre le Cancer, Region Centre (LIPIDS project of ARD2020-Biomédicaments), INSERM, Cancéropôle Grand Ouest, the association ‘CANCEN’ and Tours’ Hospital oncology association ‘ACORT’, Association Ti'Toine Normandie. DC is a doctoral fellow with CNRS, Région PACA and Fondation ARC. RR-M is a post-doctoral fellow of La Ligue contre le Cancer and Fondation de France. The microscopy was carried out in the Prism facility, ‘Plateforme Université Côte d'Azur, CNRS, Inserm, iBV, France. MG and LC are respectively doctoral fellows of Region Centre and Region Centre/INSERM. Local tumor tissue biobank BB-0033-00037 (‘CRB Santé/Tumorothèque de Brest’).

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Author notes

  1. M Gueguinou, A Chantôme, M Potier-Cartereau, L Clarysse, A Girault, Y Fourbon, G Fromont, O Mignen and C Vandier: From network ‘Ion channels and cancer-Canceropole Grand Ouest’ (IC-CGO), France, www.ic-cgo.fr.

  2. M Gueguinou, D Crottès, C Vandier and O Soriani: These authors contributed equally to this work.

Authors and Affiliations

  1. Inserm—University U1069 Nutrition, Croissance et Cancer, Tours, France

    M Gueguinou, A Chantôme, M Potier-Cartereau, L Clarysse, A Girault, Y Fourbon, G Fromont & C Vandier

  2. Université Côte d'Azur, CNRS, Inserm, iBV, France

    D Crottès, R Rapetti-Mauss, P Martin, B Pellissier, F Borgese & O Soriani

  3. Unité de Bioinfomique, Institut de Cancérologie de L'Ouest - René Gauducheau, Centre de Recherche en Cancérologie, UMR-INSERM 892, St Herblain, France

    P Jézéquel & C Guérin-Charbonnel

  4. Service d’Anatomie Pathologique, Hopital Bretonneau, CHRU Tours, Tours, France

    G Fromont

  5. Unité d’Epidémiologie et Biostatistiques (UEB), Centre Antoine Lacassagne, Nice, France

    R Schiappa & E Chamorey

  6. Department of Pathology, Inserm U1078, Brest University Hospital, Brest, France

    O Mignen & A Uguen

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  1. M Gueguinou
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Correspondence to C Vandier or O Soriani.

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Gueguinou, M., Crottès, D., Chantôme, A. et al. The SigmaR1 chaperone drives breast and colorectal cancer cell migration by tuning SK3-dependent Ca2+ homeostasis. Oncogene 36, 3640–3647 (2017). https://doi.org/10.1038/onc.2016.501

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