Store operated calcium entry is altered by the inhibition of receptors tyrosine kinase.

Noémie Emeriau,Nicolas Tajeddine,Marie De Clippele,Philippe Gailly

doi:10.18632/oncotarget.24685

Noémie Emeriau, Nicolas Tajeddine + Show 2 more

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https://doi.org/10.18632/oncotarget.24685

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Journal: Oncotarget	Publication Date: Mar 23, 2018
Citations: 10	License type: cc-by

Affiliation: Université Catholique de Louvain

Abstract

SOCE (Store-Operated Calcium Entry) is the main mechanism by which external Ca2+ enters into non-excitable cells after endoplasmic reticulum emptying. It is implicated in several processes such as proliferation and migration. Alterations in SOCE could initiate or support the development of hallmarks of cancer. In this project, we showed that disruption of the EGFR/ErbB2-dependent signalling by lapatinib and CP-724714, two inhibitors of the receptor tyrosine kinase (RTK), dramatically reduced the amplitude of the SOCE in breast cancer cells. LY294002 and MK2206, two inhibitors of the PI3K/Akt pathway, mimicked the effect of the inhibition of EGFR/ErbB2. In contrast, inhibitors of the MAPK pathway had no effect on SOCE. The involvement of EGFR/ErbB2 receptors and the PI3K/Akt pathway in the regulation of SOCE was confirmed in other cell lines derived from various cancer types. All these results showed that SOCE is positively regulated by the PI3K/Akt pathway and that this effect may be suppressed by the inhibition of the upstream RTKs. Inhibition of SOCE might therefore contribute to the anticancer effects of RTK inhibitors.

Highlights

A multitude of studies show that alterations in Ca2+ signalling initiate or support the development of hallmarks of cancer and Ca2+ channels are centrally involved in cancer cells proliferation and migration [1, 2]
We showed that disruption of the EGFR/ErbB2-dependent signalling by lapatinib and CP-724714, two inhibitors of the receptor tyrosine kinase (RTK), dramatically reduced the amplitude of the store-operated calcium entry (SOCE) in breast cancer cells
Given the fact that SOCE is involved in cancer cell proliferation and that RTKs might be, at least in some circumstances, linked to Ca2+ signalling, we have evaluated the effects of tyrosine kinase inhibitors (TKIs) or monoclonal antibodies targeting RTKs in the regulation of SOCE in ErbB2-overpressing breast cancer cell line

Summary

Introduction

A multitude of studies show that alterations in Ca2+ signalling initiate or support the development of hallmarks of cancer and Ca2+ channels are centrally involved in cancer cells proliferation and migration [1, 2]. Described by James Putney in 1986, SOCE is the main mechanism by which external Ca2+ enters into non-excitable cells [3]. Upon endoplasmic reticulum (ER) depletion in response to the activation of a G-protein coupled receptor or a receptor tyrosine kinase, stromal interaction molecule 1 (STIM1), an ER-resident membrane protein, clusters at the ER/plasma membrane junctional region, where it triggers the opening of ORAI1, a plasma membrane channel, which allows Ca2+ entry from the external medium [4,5,6]. It should be noticed that all stimuli that provoke ER emptying induce SOCE. It is possible to trigger SOCE in vitro even in cells for which specific agonists are unknown. Inhibition of SERCA pumps by thapsigargin leads to the release of Ca2+ from the ER and induces SOCE

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