Laboratory of Calciomics and Systemic Pathophysiology, Regional Centre for Biotechnology (RCB), Faridabad, Delhi-NCR, India; CSIR-Institute of Genomics and Integrative Biology (IGIB), New Delhi, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.
Laboratory of Calciomics and Systemic Pathophysiology, Regional Centre for Biotechnology (RCB), Faridabad, Delhi-NCR, India.
Cell Calcium. 2020 Sep;90:102247. doi: 10.1016/j.ceca.2020.102247. Epub 2020 Jun 26.
Ion channels in particular Calcium (Ca) 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 Ca selective channel family is Orai channels consisting of three homologs Orai1, Orai2 and Orai3. Orai channels are responsible for Ca influx across the plasma membrane in response to decrease in Endoplasmic Reticulum (ER) Ca stores. STIM1/STIM2 proteins sense the reduction in ER Ca levels and activate Orai channels for restoring ER Ca as well as for driving cellular functions. This signaling cascade is known as Store Operated Ca 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 Ca (ARC) channels or arachidonic acid metabolite Leukotriene C (LTC) regulated Ca (LRC) channels. Literature suggests that Orai3 regulates Breast, Prostate, Lung and Gastrointestinal cancers by either forming Store Operated Ca (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.
离子通道，尤其是钙（Ca）通道，通过调节细胞增殖、分化、转录调控和程序性细胞死亡等多种细胞过程，在生理学中发挥着关键作用。Orai 通道是一类具有生理意义的、高度选择性的 Ca 通道家族，由三个同源物 Orai1、Orai2 和 Orai3 组成。Orai 通道负责响应内质网 (ER) Ca 储存减少，在内质网 (ER) 钙库减少时将 Ca 内流入细胞质膜。STIM1/STIM2 蛋白感知 ER Ca 水平的降低，并激活 Orai 通道以恢复 ER Ca 并驱动细胞功能。这种信号级联反应被称为钙库操纵性钙内流（SOCE）。虽然 Orai1 是普遍存在的 SOCE 通道蛋白，但 Orai2 和 Orai3 在某些特定组织中介导 SOCE。此外，哺乳动物特异性同源物 Orai3 与 Orai1 形成异源多聚体通道，构成花生四烯酸调节钙（ARC）通道或花生四烯酸代谢产物白三烯 C（LTC）调节钙（LRC）通道。文献表明，Orai3 通过在癌细胞中形成钙库操纵性钙（SOC）或 ARC/LRC 通道来调节乳腺癌、前列腺癌、肺癌和胃肠道癌，但不在健康组织中调节。在这篇综述中，我们将讨论 Orai3 在这些癌症中的作用，并强调针对 Orai3 的治疗靶向的潜力，以更好地管理和治疗癌症。最后，我们将讨论该领域的一些关键问题，这些问题需要得到重视和进一步研究。
