TRPC1-STIM1 activation modulates transforming growth factor β-induced epithelial-to-mesenchymal transition

Anne Schaar, Pramod Sukumaran, Yuyang Sun, Archana Dhasarathy, Brij B. Singh

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

Activation of Epithelial-to-Mesenchymal Transition (EMT) is important for tumor metastasis. Although growth factors such as TGFβ and EGF have been shown to induce EMT in breast epithelial cells, the mechanism resulting in migration is not well understood. Herein, we provide evidence that Ca2+ entry into the cell, especially upon store-depletion, plays an important role in TGFβ-induced EMT by promoting cellular migration and potentially leading to metastasis. The increased migration by TGFβ in non-cancerous cells was due to the loss of E-cadherin along with a subsequent increase in N-cadherin levels. Importantly, TGFβ-treatment increases store-mediated Ca2+ entry, which was essential for the activation of calpain leading to the loss of E-cadherin and MMP activation. Inhibition of Ca2+ entry by using Ca2+ channel blocker SKF-96365, significantly decreased Ca2+ entry, decreased TGFβ- induced calpain activation, and suppressed the loss of E-cadherin along with inhibiting cell migration. Furthermore, TRPC1 function as an endogenous Ca2+ entry channel and silencing of either TRPC1 or its activator, STIM1, significantly decreased TGFβ induced Ca2+ entry, inhibited TGFβ-mediated calpain activation and cell migration. In contrast, overexpression of TRPC1 showed increased Ca2+ entry and promoted TGFβ- mediated cell migration. Moreover, increased TRPC1 expression was observed in ductal carcinoma cells. Together these results suggest that disrupting Ca2+ influx via TRPC1/STIM1 mechanism reduces calpain activity, which could restore intercellular junction proteins thereby inhibiting EMT induced motility.

Original languageEnglish (US)
Pages (from-to)80554-80567
Number of pages14
JournalOncotarget
Volume7
Issue number49
DOIs
StatePublished - 2016
Externally publishedYes

Keywords

  • Calpain
  • EMT
  • SOCE
  • TRPC1-STIM1
  • calcium

ASJC Scopus subject areas

  • Oncology

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