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Pivotal role of the lipid Raft SK3-Orai1 complex in human cancer cell migration and bone metastases.

A. Chantôme,M. Potier-Cartereau,Lucie Clarysse,G. Fromont,S. Marionneau-Lambot,M. Guéguinou,J. Pagès,C. Collin,Thibauld Oullier,A. Girault,F. Arbion,J. Haelters,P. Jaffrès,M. Pinault,P. Besson,V. Joulin,P. Bougnoux,C. Vandier

Published 2013 in Cancer Research

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.

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