SOCE and cancer: Recent progress and new perspectives

Abstract

Ca(2+) acts as a universal and versatile second messenger in the regulation of a myriad of biological processes, including cell proliferation, differentiation, migration and apoptosis. Store-operated Ca(2+) entry (SOCE) mediated by ORAI and the stromal interaction molecule (STIM) constitutes one of the major routes of calcium entry in nonexcitable cells, in which the depletion of intracellular Ca(2+) stores triggers activation of the endoplasmic reticulum (ER)-resident Ca(2+) sensor protein STIM to gate and open the ORAI Ca(2+) channels in the plasma membrane (PM). Accumulating evidence indicates that SOCE plays critical roles in cancer cell proliferation, metastasis and tumor neovascularization, as well as in antitumor immunity. We summarize herein the recent advances in our understanding of the function of SOCE in various types of tumor cells, vascular endothelial cells and cells of the immune system. Finally, the therapeutic potential of SOCE inhibitors in the treatment of cancer is also discussed.

Keywords: ORAI1; SOCE; STIM1; calcium; cancer; therapeutics.

Figure 1

Schematic diagram of SOCE mediated by ORAI1 and STIM1. (a) STIM1 protein consists of a canonical EF hand, a hidden EF hand and a SAM domain in the ER luminal domain, and CCD, SOAR and ERM domains as well as serine‐ or proline‐ and lysine‐rich clusters on the cytosolic side. (b) The ORAI1 protein contains four membrane‐spanning regions and intracellular N‐ and C‐termini. It also has a unique R/P‐rich region in the N‐terminus and a putative coiled‐coil domain in its intracellular C‐terminus. (c) The stimulation of PM receptors activates PLC, which leads to the production of the second messenger IP3. IP3 binds to the IP3R and elicits rapid Ca²⁺ release from the ER lumen. STIM1 senses Ca²⁺ decrease in ER and undergoes conformational changes to mediate ORAI gating, which results in Ca²⁺ influx through ORAI channels. The Ca²⁺ increase activates NFAT and a number of other transcription factors such as NF‐κB and CREB, among others, which play crucial roles in cancer cells, endothelial cells, cells of the immune system and other nonhematopoietic cells.

Figure 2

Proposed roles of SOCE in cancer. In tumor cells, SOCE promotes cancer cell proliferation via the upregulation of Cdc25C and the downregulation of p21. It also promotes cancer cell metastasis via the modulation of calpain‐ and Pyk2‐mediated focal adhesion turnover or through upregulating the expression of COX‐2, PGE2 and autotoxin. SOCE also contributes to drug resistance through an enhancement of AKT activity. In cancer cells, SOCE boosts the secretion of VEGF, which facilitates endothelial cell proliferation, angiogenesis and tumor growth. SOCE‐mediated chronic inflammation through activation of Th17 cells is speculated to promote tumor growth. However, in NK, CD8⁺ T and Th1 cells, SOCE is required to inhibit tumor progression.