Role of Orai3 in the Pathophysiology of Cancer

Abstract

The mammalian exclusive Orai3 channel participates in the generation and/or modulation of two independent Ca²⁺ currents, the store-operated current, I_crac, 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 I_arc, 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.

Keywords: calcium entry; cancer; orai1; orai3.

Figure 1

Schematic structure of human Orai1, Orai2, and Orai3 and Orai subunit architecture. R/L, arginine and lysine-rich (positively charged) region; P, proline-rich region; PM, plasma membrane; TM, transmembrane domain.

Figure 2

Overview of Orai3 functional role in cancer cells. Orai3 expression has been reported to be up-regulated in different cancer cell types, including those from estrogen receptor-positive breast cancer (ER + BC), prostate cancer (PC), non-small cell lung cancer (NSCLC) cells, colorectal cancer (CC), pancreatic ductal adenocarcinoma (PDAC) as well as tipifarnib-sensitive acute myeloid leukemia and multiple myeloma (L and MM). Except in leukemia and multiple myeloma cells, Orai3 plays a relevant role in the development or maintenance of different cancer hallmarks, such as cell cycle progression and proliferation, apoptosis resistance and survival and migration and colony formation. In tipifarnib-sensitive leukemia and multiple myeloma cells Orai3-mediated Ca²⁺ influx is activated by tipifarnib leading to Ca²⁺ overload and loss of cell viability. PI3K, phosphatidylinositol 3-kinase; ARC channels, arachidonic acid-regulated calcium channels; ERK, extracellular signal-regulated kinase; sgk-1, serine/threonine-protein kinase-1; p53 degr., p53 degradation; cdk-4, cyclin-dependent kinase-4; CSC, cancer stem cells; HIP1/2α, hypoxia inducible factor 1/2α; ↑ means overexpression or activation and ↓ means inhibition.