The calcium channel proteins ORAI3 and STIM1 mediate TGF-β induced Snai1 expression

Atrayee Bhattacharya, Janani Kumar, Kole Hermanson, Yuyang Sun, Humaira Qureshi, Danielle Perley, Adam Scheidegger, Brij B Singh, Archana Dhasarathy

Research output: Contribution to journalArticle

5 Scopus citations

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 epithelialmesenchymal 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.

Original languageEnglish (US)
Pages (from-to)29468-29483
Number of pages16
JournalOncotarget
Volume9
Issue number50
DOIs
StatePublished - Jun 29 2018

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Keywords

  • Calcium
  • EMT
  • ORAI3
  • SNAIL
  • TGF-β

ASJC Scopus subject areas

  • Oncology

Cite this

Bhattacharya, A., Kumar, J., Hermanson, K., Sun, Y., Qureshi, H., Perley, D., Scheidegger, A., Singh, B. B., & Dhasarathy, A. (2018). The calcium channel proteins ORAI3 and STIM1 mediate TGF-β induced Snai1 expression. Oncotarget, 9(50), 29468-29483. https://doi.org/10.18632/oncotarget.25672