ABSTRACT
Store operated Ca2+ entry (SOCE) mediated by Orai1/2/3 channels is a highly regulated and ubiquitous Ca2+ influx pathway. Although the role of Orai1 channels is well studied, the significance of Orai2/3 channels is still emerging in nature. In this study, we performed extensive bioinformatic analysis of publicly available datasets and observed that Orai3 expression is inversely associated with the mean survival time of PC patients. Orai3 expression analysis in a battery of PC cell lines corroborated its differential expression profile. We then carried out thorough Ca2+ imaging experiments in six PC cell lines and found that Orai3 forms a functional SOCE channel in PC cells. Our in vitro functional assays show that Orai3 regulates PC cell cycle progression, apoptosis and migration. Most importantly, our in vivo xenograft studies demonstrate a critical role of Orai3 in PC tumor growth and secondary metastasis. Mechanistically, Orai3 controls G1 phase progression, matrix metalloproteinase expression and epithelial-mesenchymal transition in PC cells. Taken together, this study for the first-time reports that Orai3 drives aggressive phenotypes of PC cells, i.e., migration in vitro and metastasis in vivo. Considering that Orai3 overexpression leads to poor prognosis in PC patients, it appears to be a highly attractive therapeutic target.
ABSTRACT
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.
