Abstract
The mammalian exclusive Orai3 channel participates in the generation and/or modulation of two independent Ca2+ currents, the store-operated current, Icrac, involving functional interactions between the stromal interaction molecules (STIM), STIM1/STIM2, and Orai1/Orai2/Orai3, as well as the store-independent arachidonic acid (AA) (or leukotriene C4)-regulated current Iarc, which involves Orai1, Orai3 and STIM1. Overexpression of functional Orai3 has been described in different neoplastic cells and cancer tissue samples as compared to non-tumor cells or normal adjacent tissue. In these cells, Orai3 exhibits a cell-specific relevance in Ca2+ influx. In estrogen receptor-positive breast cancer cells and non-small cell lung cancer (NSCLC) cells store-operated Ca2+ entry (SOCE) is strongly dependent on Orai3 expression while in colorectal cancer and pancreatic adenocarcinoma cells Orai3 predominantly modulates SOCE. On the other hand, in prostate cancer cells Orai3 expression has been associated with the formation of Orai1/Orai3 heteromeric channels regulated by AA and reduction in SOCE, thus leading to enhanced proliferation. Orai3 overexpression is associated with supporting several cancer hallmarks, including cell cycle progression, proliferation, migration, and apoptosis resistance. This review summarizes the current knowledge concerning the functional role of Orai3 in the pathogenesis of cancer.
Highlights
The Orai channels are the pore-forming proteins that underlie the Ca2+ releaseactivated Ca2+ (CRAC) channels, the best characterized store-operated channels activated by the endoplasmic reticulum Ca2+ sensor STIM1 and its homolog STIM2 that mediates store-operated Ca2+ entry (SOCE)
Orai3 is predominantly overexpressed as compared to non-tumor cells but its role in SOCE/Ca2+ influx differs in the different cancer cell types
The functional role of Orai2 and Orai3 in SOCE is mostly associated with the modulation of the magnitude of Ca2+ influx by heteromultimerization with Orai1 subunits into the CRAC channels [22]
Summary
The Orai channels are the pore-forming proteins that underlie the Ca2+ releaseactivated Ca2+ (CRAC) channels, the best characterized store-operated channels activated by the endoplasmic reticulum Ca2+ sensor STIM1 and its homolog STIM2 that mediates store-operated Ca2+ entry (SOCE). It has been reported that the Orai specific proline/arginine-rich domains located in the N-terminus are essential for current reactivation, while the second, cytosolic, loop seems to be involved in fast and slow gating processes [19]. The N-terminus of Orai, the region between amino acids 1–38, which is remarkably different from the corresponding residues in Orai, is critical for the selective activation of ARC channels by AA [11]. Å. The effect of 2-APB on Orai activation has been reported to be dependent on the E165 residue located in the third transmembrane domain, as the Orai3-E165Q mutant resulted in permeation properties similar to that observed by 2-APB stimulation of Orai and almost completely abolished the stimulatory effect of 2-APB [29]. Overexpression of functional Orai has been reported in several neoplastic cells where this channel has been associated to the development or support of several cellular activities, leading to cancer progression
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