title: Pivotal role of the lipid Raft SK3-Orai1 complex in human cancer cell migration and bone metastases.
abstract: The SK3 channel, a potassium channel, was recently shown to control cancer cell migration, a critical step in metastasis outgrowth. Here, we report that expression of the SK3 channel was markedly associated with bone metastasis. The SK3 channel was shown to control constitutive Ca(2+) entry and cancer cell migration through an interaction with the Ca(2+) channel Orai1. We found that the SK3 channel triggers an association with the Orai1 channel within lipid rafts. This localization of an SK3-Orai1 complex seemed essential to control cancer cell migration. This suggests that the formation of this complex in lipid rafts is a gain-of-function, because we showed that none of the individual proteins were able to promote the complete phenotype. We identified the alkyl-lipid Ohmline as a disrupting agent for SK3-Orai1 lipid raft localization. Upon Ohmline treatment, the SK3-Orai1 complex moved away from lipid rafts, and SK3-dependent Ca(2+) entry, migration, and bone metastases were subsequently impaired. The colocalization of SK3 and Orai1 in primary human tumors and bone metastases further emphasized the clinical relevance of our observations. Targeting SK3-Orai1 in lipid rafts may inaugurate innovative approaches to inhibit bone metastases.
authors.affiliation: Inserm, UMR1069, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Chantôme
authors.forename: Marie
authors.initials: M
authors.lastname: Potier-Cartereau
authors.forename: Lucie
authors.initials: L
authors.lastname: Clarysse
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Fromont
authors.forename: Séverine
authors.initials: S
authors.lastname: Marionneau-Lambot
authors.forename: Maxime
authors.initials: M
authors.lastname: Guéguinou
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Pagès
authors.forename: Christine
authors.initials: C
authors.lastname: Collin
authors.forename: Thibauld
authors.initials: T
authors.lastname: Oullier
authors.forename: Alban
authors.initials: A
authors.lastname: Girault
authors.forename: Flavie
authors.initials: F
authors.lastname: Arbion
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Haelters
authors.forename: Paul-Alain
authors.initials: PA
authors.lastname: Jaffrès
authors.forename: Michelle
authors.initials: M
authors.lastname: Pinault
authors.forename: Pierre
authors.initials: P
authors.lastname: Besson
authors.forename: Virginie
authors.initials: V
authors.lastname: Joulin
authors.forename: Philippe
authors.initials: P
authors.lastname: Bougnoux
authors.forename: Christophe
authors.initials: C
authors.lastname: Vandier
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000378:metabolism* / Q000556:secondary; D015220:Calcium Channels / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D021962:Membrane Microdomains / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000473:pathology; D009374:Neoplasms, Experimental / Q000378:metabolism* / Q000556:secondary*; D000071740:ORAI1 Protein; D018408:Patch-Clamp Techniques; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*
chemical_list: D015220:Calcium Channels; C406328:KCNN3 protein, human; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; D051640:Small-Conductance Calcium-Activated Potassium Channels