Orai3: Oncochannel with therapeutic potential

Ion channels in particular Calcium (Ca²⁺) channels play a critical role in physiology by regulating plethora of cellular processes ranging from cell proliferation, differentiation, transcriptional regulation and programmed cell death. One such physiologically important and highly Ca²⁺ selective channel family is Orai channels consisting of three homologs Orai1, Orai2 and Orai3. Orai channels are responsible for Ca²⁺ influx across the plasma membrane in response to decrease in Endoplasmic Reticulum (ER) Ca²⁺ stores. STIM1/STIM2 proteins sense the reduction in ER Ca²⁺ levels and activate Orai channels for restoring ER Ca²⁺ as well as for driving cellular functions. This signaling cascade is known as Store Operated Ca²⁺ Entry (SOCE). Although Orai1 is the ubiquitous SOCE channel protein, Orai2 and Orai3 mediate SOCE in certain specific tissues. Further, mammalian specific homolog Orai3 forms heteromultimeric channel with Orai1 for constituting Arachidonic acid regulated Ca²⁺ (ARC) channels or arachidonic acid metabolite Leukotriene C₄ (LTC₄) regulated Ca²⁺ (LRC) channels. Literature suggests that Orai3 regulates Breast, Prostate, Lung and Gastrointestinal cancers by either forming Store Operated Ca²⁺ (SOC) or ARC/LRC channels in the cancerous cells but not in healthy tissue. In this review, we would discuss the role of Orai3 in these cancers and would highlight the potential of therapeutic targeting of Orai3 for better management and treatment of cancer. Finally, we will deliberate on key outstanding questions in the field that demand critical attention and further studies.