Physiological functions of calcium signaling via Orai1 in cancer.

Intracellular calcium (Ca²⁺) signaling regulates many cellular functions, including cell proliferation and migration, in both normal cells and cancer cells. Store-operated Ca²⁺ entry (SOCE) is a major mechanism by which Ca²⁺ is imported from the extracellular space to the intracellular space, especially in nonexcitable cells. Store-operated Ca²⁺ entry (SOCE) is also a receptor-regulated Ca²⁺ entry pathway that maintains Ca²⁺ homeostasis by sensing reduced Ca²⁺ levels in the endoplasmic reticulum (ER). In general, the activation of G protein-coupled receptors (GPCRs) or immunoreceptors, such as T-cell, B-cell and Fc receptors, results in the production of inositol 1,4,5-trisphosphate (IP₃). IP₃ binds to IP₃ receptors located in the ER membrane. The, IP₃ receptors in the ER membrane trigger a rapid and transient release of Ca²⁺ from the ER store. The resulting depletion of ER Ca²⁺ concentrations is sensed by the EF-hand motif of stromal interaction molecule (STIM), i.e., calcium sensor, which then translocates to the plasma membrane (PM). STIM interacts with Orai Ca²⁺ channel subunits (also known as CRACM1) on the PM, leading to Ca²⁺ influx from the extracellular space to increase intracellular Ca²⁺ concentrations. The physiological functions of Orai and STIM have been studied mainly with respect to their roles in the immune system. Based on numerous previous studies, Orai channels (Orai1, Orai2 and Orai3 channels) control Ca²⁺ release-activated Ca²⁺ (CRAC) currents and contribute to SOCE currents in other types of cells, including various cancer cells. There are many reports that Orai1 is involved in cell proliferation, migration, metastasis, apoptosis and epithelial-mesenchymal transition (EMT) in various cancers. We previously found that Orai1 plays important roles in cell apoptosis and migration in melanoma. Recently, we reported novel evidence of Orai1 in human oral squamous cell carcinoma (OSCC) cells and human cardiac fibroblasts (HCFs). In this review, we present multiple physiological functions of Orai1 in various cancer cells and cardiac fibroblasts, including our findings.