The calcium channel proteins ORAI3 and STIM1 mediate TGF-β induced Snai1 expression
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Atrayee Bhattacharya1, Janani Kumar1,2, Kole Hermanson1, Yuyang Sun1,3, Humaira Qureshi1,4, Danielle Perley1, Adam Scheidegger1, Brij B. Singh1,3 and Archana Dhasarathy1
1Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USA
2Present address: MD Anderson Cancer Center, Mitchell Basic Sciences Research Building, TX, USA
3Present address: UT Health Science Center, San Antonio, San Antonio, TX, USA
4Present address: Habib University, University Avenue, Gulistan-e-Jauhar, Karachi, Pakistan
Archana Dhasarathy, email: [email protected]
Keywords: calcium; TGF-β; SNAIL; EMT; ORAI3
Received: March 15, 2018 Accepted: June 09, 2018 Published: June 29, 2018
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 Snai1 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 Snai1 gene activation. We determined that this increased Snai1 transcription involves signaling through the AKT pathway and subsequent binding of NF-κB (p65) at the Snai1 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 Snai1 transcription. These results suggest that calcium channels differentially regulate cell migration and Snai1 transcription, indicating that each of these steps could be targeted to ensure complete blockade of cancer progression.
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