Abstract
The ubiquitous second messenger Ca2+ has been demonstrated to play an important role in cancer progression. Store-operated Ca2+ entry (SOCE) is the main Ca2+ entry pathway regulating intracellular Ca2+ concentration in a variety of cancer types. The present study aimed to explore the specific mechanisms of SOCE in the processes of glioma migration and invasion. The expression of Orai1, a key component of SOCE, was examined in glioma samples and glioma cell lines by immunohistochemistry and western blot analysis. Both pharmacological intervention and RNA interference were employed to investigate the role of SOCE in glioma cell migration and invasion in vitro. The intracellular Ca2+ was certified through Fluo-4/AM based Ca2+ measurement. The effect of SOCE on cell viability, migration, and invasion was explored by methyl thiazolyl tetrazolium (MTT) assay, wound healing assay, transwell invasion assay. Western blot analysis and immunofluorescence assay were used to observe the changes of downstream related protein and cell morpholog. Orai1 expression was elevated in glioma tissues and several glioma cell lines compared with non-neoplastic brain tissues. Either inhibition of SOCE by a pharmacological inhibitor or Orai1 downregulation suppressed glioma cell migration and invasion. However, re-expression of Orai1 could rescue glioma cell motility. Furthermore, phosphorylation of proline-rich tyrosine kinase 2 (Pyk2) participated in the mechanisms by which SOCE regulated focal adhesion turnover and epithelial-to-mesenchymal (−like) transition in glioma cells, both of which are considered to be critical for tumor progression. The SOCE-Pyk2 pathway is essential for glioma migration and invasion. The study indicates the potential value of Orai1 as a molecular target for anti-invasion therapy.
Highlights
The ubiquitous second messenger Ca2+ has been demonstrated to play an important role in cancer progression
The data showed that non-neoplastic brain tissues expressed low levels of Orai1, but Orai1 expression was positively correlated with the World Health Organization (WHO) grading of gliomas
The major findings of this study are: (1) blockage of Store-operated Ca2+ entry (SOCE) by a pharmacological inhibitor (SKF96365) or Orai1 downregulation can suppress glioma cell invasion and migration; (2) SKF96365 and Orai1 downregulation induce large focal adhesions and inhibit EMT-like in glioma cells; (3) SKF96365 and Orai1 downregulation reduce the phosphorylation of proline-rich tyrosine kinase 2 (Pyk2); (4) re-expression of Orai1 can rescue all of the changes described above resulting from Orai1 downregulation; and (5) Pyk2 silencing inhibits cell invasion, induces large focal adhesions, and inhibits EMT-like in glioma cells again compared with the Orai1 rescue group
Summary
The ubiquitous second messenger Ca2+ has been demonstrated to play an important role in cancer progression. Store-operated Ca2+ entry (SOCE) is the main Ca2+ entry pathway regulating intracellular Ca2+ concentration in a variety of cancer types. The ubiquitous intracellular second messenger Ca2+ plays an important role in many fundamental physiological processes, including cell excitability, exocytosis, motility, apoptosis, and transcription [3]. Store-operated Ca2+ entry (SOCE), which is initiated by the depletion of intracellular Ca2+ stores, is an important pathway in nonexcitable cells [6]. SOCE is mediated by store-operated Ca2+ channels (SOCs), including stromal interacting molecule-1 (STIM1) and Orai. The specific mechanisms include SOCE-mediated induction of a higher rate of focal adhesion turnover and accelerated migration velocity of cancer cells, whereas a reduction in SOCE resulted in larger focal adhesions, slowing their turnover and increasing adherence. Similar studies were performed in cervical cancer and hepatocarcinoma, and the results support the above conclusion [8,9]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
