title: The SigmaR1 chaperone drives breast and colorectal cancer cell migration by tuning SK3-dependent Ca2+homeostasis.
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.
authors.affiliation: Inserm-University U1069 Nutrition, Croissance et Cancer, Tours, France.
authors.forename: M
authors.initials: M
authors.lastname: Gueguinou
authors.affiliation: Université Côte d'Azur, CNRS, Inserm, iBV, France.
authors.forename: D
authors.initials: D
authors.lastname: Crottès
authors.affiliation: Inserm-University U1069 Nutrition, Croissance et Cancer, Tours, France.
authors.forename: A
authors.initials: A
authors.lastname: Chantôme
authors.affiliation: Université Côte d'Azur, CNRS, Inserm, iBV, France.
authors.forename: R
authors.initials: R
authors.lastname: Rapetti-Mauss
authors.affiliation: Inserm-University U1069 Nutrition, Croissance et Cancer, Tours, France.
authors.forename: M
authors.initials: M
authors.lastname: Potier-Cartereau
authors.affiliation: Inserm-University U1069 Nutrition, Croissance et Cancer, Tours, France.
authors.forename: L
authors.initials: L
authors.lastname: Clarysse
authors.affiliation: Inserm-University U1069 Nutrition, Croissance et Cancer, Tours, France.
authors.forename: A
authors.initials: A
authors.lastname: Girault
authors.affiliation: Inserm-University U1069 Nutrition, Croissance et Cancer, Tours, France.
authors.forename: Y
authors.initials: Y
authors.lastname: Fourbon
authors.affiliation: Unité de Bioinfomique, Institut de Cancérologie de L'Ouest - René Gauducheau, Centre de Recherche en Cancérologie, UMR-INSERM 892, St Herblain, France.
authors.forename: P
authors.initials: P
authors.lastname: Jézéquel
authors.affiliation: Unité de Bioinfomique, Institut de Cancérologie de L'Ouest - René Gauducheau, Centre de Recherche en Cancérologie, UMR-INSERM 892, St Herblain, France.
authors.forename: C
authors.initials: C
authors.lastname: Guérin-Charbonnel
authors.affiliation: Inserm-University U1069 Nutrition, Croissance et Cancer, Tours, France.|Service d'Anatomie Pathologique, Hopital Bretonneau, CHRU Tours, Tours, France.
authors.forename: G
authors.initials: G
authors.lastname: Fromont
authors.affiliation: Université Côte d'Azur, CNRS, Inserm, iBV, France.
authors.forename: P
authors.initials: P
authors.lastname: Martin
authors.affiliation: Université Côte d'Azur, CNRS, Inserm, iBV, France.
authors.forename: B
authors.initials: B
authors.lastname: Pellissier
authors.affiliation: Unité d'Epidémiologie et Biostatistiques (UEB), Centre Antoine Lacassagne, Nice, France.
authors.forename: R
authors.initials: R
authors.lastname: Schiappa
authors.affiliation: Unité d'Epidémiologie et Biostatistiques (UEB), Centre Antoine Lacassagne, Nice, France.
authors.forename: E
authors.initials: E
authors.lastname: Chamorey
authors.affiliation: Department of Pathology, Inserm U1078, Brest University Hospital, Brest, France.
authors.forename: O
authors.initials: O
authors.lastname: Mignen
authors.affiliation: Department of Pathology, Inserm U1078, Brest University Hospital, Brest, France.
authors.forename: A
authors.initials: A
authors.lastname: Uguen
authors.affiliation: Université Côte d'Azur, CNRS, Inserm, iBV, France.
authors.forename: F
authors.initials: F
authors.lastname: Borgese
authors.affiliation: Inserm-University U1069 Nutrition, Croissance et Cancer, Tours, France.
authors.forename: C
authors.initials: C
authors.lastname: Vandier
authors.affiliation: Université Côte d'Azur, CNRS, Inserm, iBV, France.
authors.forename: O
authors.initials: O
authors.lastname: Soriani
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D045744:Cell Line, Tumor; D002465:Cell Movement; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D005260:Female; D006801:Humans; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D000071740:ORAI1 Protein / Q000235:genetics / Q000378:metabolism; D017480:Receptors, sigma / Q000235:genetics / Q000378:metabolism*; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000235:genetics / Q000378:metabolism*; D000097605:Sigma-1 Receptor
chemical_list: D002118:Calcium; D009363:Neoplasm Proteins; D000071740:ORAI1 Protein; D017480:Receptors, sigma; D051640:Small-Conductance Calcium-Activated Potassium Channels; D000097605:Sigma-1 Receptor; C406328:KCNN3 protein, human; C510746:ORAI1 protein, human