Original association of ion transporters mediates the ECM-induced breast cancer cell survival: Kv10.1-Orai1-SPCA2 partnership

Marta Peretti,Mehdi Badaoui,Riad Tebbakha,Hamid Morjani,Halima Ouadid-Ahidouch,Laurence Van Gulick,Henri Sevestre,Alban Girault,Marie-Pierre Mabille

doi:10.1038/s41598-018-37602-7

Marta Peretti, Mehdi Badaoui + Show 7 more

Open Access

https://doi.org/10.1038/s41598-018-37602-7

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Abstract

In the last years it has been shown that many components of tumor microenvironment (TM) can induce cell signaling that permit to breast cancer cells (BC) to maintain their aggressiveness. Ion channels have a role in mediating TM signal; recently we have demonstrated a functional collaboration between Kv10.1 and Orai1 channels in mediating the pro-survival effect of collagen 1 on BC cells. Here we show how SPCA2 (Secretory Pathway Ca2+ ATPase) has a role in this process and is able to support survival and proliferation induced by collagen 1. By participating to an auto-sustaining loop, SPCA2 enhances membrane expression of Kv10.1 and Orai1; the activity of every component of this trio is necessary to mediate a store independent calcium entry (SICE). This SICE is fundamental to maintain both the activation of the pro-survival pathway and the membrane localization and consequently the activity of the two channels. Moreover, the three proteins and the collagen receptor DDR1 are overexpressed only in aggressive tumors tissues. In this work, we propose a novel association between SPCA2, Kv10.1 and Orai1 involved in mediating transduction signals from TM to the BC cells that can be potentially exploited in the search of novel therapeutic targets specific to tumor tissues.

Highlights

In the last years it has been shown that many components of tumor microenvironment (TM) can induce cell signaling that permit to breast cancer cells (BC) to maintain their aggressiveness
Feng and colleagues have demonstrated that SPCA2 (Secretory Pathway Ca2+-ATPase 2) is able to interact with and activate Orai[1], triggering a calcium entry that does not depend on Stim[1] and intracellular calcium stores’ depletion and sustaining cells proliferation
We recently demonstrated that Kv10.1 and Orai[1] are involved in the regulation of collagen-induced survival of the BC cell line MCF-7

Summary

Introduction

In the last years it has been shown that many components of tumor microenvironment (TM) can induce cell signaling that permit to breast cancer cells (BC) to maintain their aggressiveness. By participating to an auto-sustaining loop, SPCA2 enhances membrane expression of Kv10.1 and Orai[1]; the activity of every component of this trio is necessary to mediate a store independent calcium entry (SICE) This SICE is fundamental to maintain both the activation of the pro-survival pathway and the membrane localization and the activity of the two channels. Orai[1] is a calcium channel mainly known for its involvement in Store Operated Calcium entry (SOCE); this role has been shown to be able to sustain BC cells migration[15,17] It has been underlined a new store-independent (SICE) activation of Orai[118–20]. Feng and colleagues have demonstrated that SPCA2 (Secretory Pathway Ca2+-ATPase 2) is able to interact with and activate Orai[1], triggering a calcium entry that does not depend on Stim[1] and intracellular calcium stores’ depletion and sustaining cells proliferation. The regulation of Orai[1] by SPCA2 is not associated with the Ca2+ pump activity of SPCA218

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