Abstract
Orai channels have been associated with cell proliferation, survival and metastasis in several cancers. The present study investigates the expression and the role of Orai3 in cell proliferation in non-small cell lung cancer (NSCLC). We show that Orai3 is over-expressed in cancer tissues as compared to the non-tumoral ones. Furthermore, Orai3 staining is stronger in high grade tumors. Pharmacological inhibition or knockdown of Orai3 significantly reduced store operated calcium entry (SOCE), inhibited cell proliferation and arrested cells of two NSCLC cell lines in G0/G1 phase. These effects were concomitant with a down-regulation of cyclin D1, cyclin E, CDK4 and CDK2 expression. Moreover, Orai3 silencing decreased Akt phosphorylation levels. In conclusion, Orai3 constitutes a native SOCE pathway in NSCLC that controls cell proliferation and cell cycle progression likely via Akt pathway.
Highlights
Calcium is a key messenger that regulates proliferation, apoptosis, migration and invasion, which are the main mechanisms implicated in cancer progression [1,2]
We demonstrate that Orai3 expression is up-regulated in lung cancer tissues, correlates with high tumor grade, and Orai3mediated Ca2+ entry is crucial to non-small cell lung cancer (NSCLC) cell proliferation
These results provide evidence that Orai3 is overexpressed in lung adenocarcinoma and the level of its expression correlates with high tumor grade
Summary
Calcium is a key messenger that regulates proliferation, apoptosis, migration and invasion, which are the main mechanisms implicated in cancer progression [1,2]. It controls G1 progression, G1/S and G2/M transition phases by regulating expression of several calcium-dependent signaling pathways, such as calmodulin, CaM-Kinase, and calcineurin [3,4,5]. Store-operated Ca2+ entry (SOCE) is the main route that drives most Ca2+-dependent signaling cascades [6,7,8]. Only three recent studies have shown the involvement of Orai and TRPC1 in SOCE in lung cancer A549 cell line [16,17].
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