The calcium channel proteins ORAI3 and STIM1 mediate TGF-β induced<i>Snai1</i>expression

Abstract

Calcium influx into cells via plasma membrane protein channels is tightly regulated to maintain cellular homeostasis. Calcium channel proteins in the plasma membrane and endoplasmic reticulum have been linked to cancer, specifically during the epithelial-mesenchymal transition (EMT), a cell state transition process implicated in both cancer cell migration and drug resistance. The transcription factor SNAI1 (SNAIL) is upregulated during EMT and is responsible for gene expression changes associated with EMT, but the calcium channels required for <i>Snai1</i> expression remain unknown. In this study, we show that blocking store-operated calcium entry (SOCE) with 2-aminoethoxydiphenylborane (2APB) reduces cell migration but, paradoxically, increases the level of TGF-β dependent <i>Snai1</i> gene activation. We determined that this increased <i>Snai1</i> transcription involves signaling through the AKT pathway and subsequent binding of NF-κB (p65) at the <i>Snai1</i> promoter in response to TGF-β. We also demonstrated that the calcium channel protein ORAI3 and the stromal interaction molecule 1 (STIM1) are required for TGF-β dependent <i>Snai1</i> transcription. These results suggest that calcium channels differentially regulate cell migration and <i>Snai1</i> transcription, indicating that each of these steps could be targeted to ensure complete blockade of cancer progression.