Blockage of LMP1-modulated store-operated Ca2+ entry reduces metastatic potential in nasopharyngeal carcinoma cell

• DOI: 10.1016/j.canlet.2015.02.032
• Publication Date: 2015-02-16T17:33:38Z
• Authors: Jiazhang Wei; Jinyan Zhang; Yongfeng Si; Masamitsu Kanada; Zhe Zhang; Susumu Terakawa; Hiroshi Watanabe
• Keywords: 0301 basic medicine; Nasopharyngeal Neoplasms; Mice, SCID; Neoplastic Cells, Circulating; 3. Good health; Animals, Genetically Modified; Viral Matrix Proteins; Mice; 03 medical and health sciences; Cell Line, Tumor; Human Umbilical Vein Endothelial Cells; Animals; Heterografts; Humans; Calcium; Calcium Signaling; Neoplasm Metastasis; Zebrafish

Epstein-Barr virus (EBV)-encoded latent membrane proteins (LMPs) expedite progression of EBV-relevant cancers. Of the full set of LMPs, latent membrane protein 1 (LMP1) was identified to uniquely augment store-operated Ca(2+) entry (SOCE). Previously, we reported that the suppression of SOCE exhibited inhibitory effects on cell migration and the extravasation from vasculature in EBV-negative nasopharyngeal carcinoma (NPC) cells. In this follow-up study, we aimed to expand our understanding of the modulation of SOCE by LMP1 and test the possibility that blockage of LMP1-modulated SOCE affects the LMP1-promoted metastatic potential. Here we showed that suppressions of the LMP1-boosted SOCE blunted the LMP1-promoted cell migration, VEGF-mediated angiogenesis and permeabilization in vitro. Blockage of SOCE inhibited vasculature-invasion of circulating cells and distant metastatic colonization in vivo. Notably, utilizing VEGFR2-EGFP-tag zebrafish we revealed that the LMP1-expressing cells arrested in a small-caliber vessel mobilized surrounding endothelial cells to facilitate vasculature-invasion. Thus, the LMP1-boosted SOCE promotes metastatic potential of NPC cells by solidifying their collaborations with the nearby non-cancer cells through the manipulation of oncogenic Ca(2+) signaling. Our study highlights the advantage of using both conventional mammal and transgenic zebrafish for developing a novel therapeutic strategy targeting the multiple steps of invasion-metastasis cascade.