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      Store-operated Ca 2+ entry regulates glioma cell migration and invasion via modulation of Pyk2 phosphorylation

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          Abstract

          Background

          The ubiquitous second messenger Ca 2+ has been demonstrated to play an important role in cancer progression. Store-operated Ca 2+ entry (SOCE) is the main Ca 2+ entry pathway regulating intracellular Ca 2+ 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.

          Methods

          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 Ca 2+ was certified through Fluo-4/AM based Ca 2+ 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.

          Results

          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.

          Conclusions

          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.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s13046-014-0098-1) contains supplementary material, which is available to authorized users.

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          Most cited references22

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          Calcium signaling.

          Calcium ions (Ca(2+)) impact nearly every aspect of cellular life. This review examines the principles of Ca(2+) signaling, from changes in protein conformations driven by Ca(2+) to the mechanisms that control Ca(2+) levels in the cytoplasm and organelles. Also discussed is the highly localized nature of Ca(2+)-mediated signal transduction and its specific roles in excitability, exocytosis, motility, apoptosis, and transcription.
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            Orai1 and STIM1 are critical for breast tumor cell migration and metastasis.

            Tumor metastasis is the primary cause of death of cancer patients. Understanding the molecular mechanisms underlying tumor metastasis will provide potential drug targets. We report here that Orai1 and STIM1, both of which are involved in store-operated calcium entry, are essential for breast tumor cell migration in vitro and tumor metastasis in mice. Reduction of Orai1 or STIM1 by RNA interference in highly metastatic human breast cancer cells or treatment with a pharmacological inhibitor of store-operated calcium channels decreased tumor metastasis in animal models. Our data demonstrate a role for Orai1 and STIM1 in tumor metastasis and suggest store-operated calcium entry channels as potential cancer therapeutic targets.
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              Calcium in tumour metastasis: new roles for known actors.

              In most cases, metastasis, not the primary tumour per se, is the main cause of mortality in cancer patients. In order to effectively escape the tumour, enter the circulation and establish secondary growth in distant organs cancer cells must develop an enhanced propensity to migrate. The ubiquitous second messenger Ca²⁺ is a crucial regulator of cell migration. Recently, a number of known molecular players in cellular Ca²⁺ homeostasis, including calcium release-activated calcium channel protein 1 (ORAI1), stromal interaction molecule 1 (STIM1) and transient receptor potential (TRP) channels, have been implicated in tumour cell migration and the metastatic cell phenotype. We discuss how these developments have increased our understanding of the Ca²⁺ dependence of pro-metastatic behaviours.
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                Author and article information

                Contributors
                xjtjmed@163.com
                823133931@qq.com
                770471066@qq.com
                347989188@qq.com
                13920973912@126.com
                yshpvip@sina.com
                lyinrain@126.com
                ydenny@yahoo.com
                Journal
                J Exp Clin Cancer Res
                J. Exp. Clin. Cancer Res
                Journal of Experimental & Clinical Cancer Research : CR
                BioMed Central (London )
                0392-9078
                1756-9966
                30 November 2014
                30 November 2014
                2014
                : 33
                : 1
                : 98
                Affiliations
                [ ]Department of Neurosurgery, Tianjin Medical University General Hospital, 154# Anshan Road, Tianjin, 300052 China
                [ ]Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Tianjin, 300052 China
                Article
                98
                10.1186/s13046-014-0098-1
                4258251
                25433371
                6f9adf87-4ddb-496b-a357-69c4f50094e5
                © Zhu et al.; licensee BioMed Central Ltd. 2014

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 9 October 2014
                : 14 November 2014
                Categories
                Research
                Custom metadata
                © The Author(s) 2014

                Oncology & Radiotherapy
                store-operated ca2+ entry,glioma,focal adhesion turnover,epithelial-to-mesenchymal (−like) transition,proline-rich tyrosine kinase 2

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