Store-operated calcium entry-based targets for novel cancer therapeutic development

Store-operated calcium entry (SOCE) is the major mechanism for cellular calcium homeostasis that is ubiquitous across cell types and is responsible for replenishing Ca²⁺ in the endoplasmic reticulum. The major calcium channel that facilitates this role is Orai1. Orai1 is regulated by proteins that interact with either its N- or C-terminus. Stromal interaction molecule 1 (STIM1) is an activator of Orai1 that binds to Orai1's C-terminus, causing the channel to open and allow for Ca²⁺ influx. Together, Orai1 and STIM1 constitute a calcium release-activated calcium channel that is critical for SOCE. Alternatively, adenylyl cyclase type 8 (AC8) binds to Orai1's N-terminus, causing the Orai1 channel to close after phosphorylation by protein kinase A. Other proteins also interact with Orai1 to elicit modulatory effects and influence the gating properties of this channel. As SOCE is critical for cellular Ca²⁺ balance and calcium-sensitive cellular functions, impairment of Orai1 function by restricting its ability to form normal protein-protein interactions (PPIs) can be deleterious and lead to pathologies. It has been discovered that overexpression of Orai1 and AC8 leads to proliferation of triple negative breast cancer cells through mechanisms dependent on Ca²⁺ signaling. Thus, PPIs involving Orai1 can be approached as therapeutic targets in diseases that arise from aberrant Ca²⁺ signaling. Orai1 PPIs can serve as targets for diseases that currently lack targeted therapies, such as triple negative breast cancer. This review examines Orai1 PPIs with STIM1 and AC8, discusses the relevance of these PPIs in cancer, and reviews the landscape of Orai1 inhibitors. SIGNIFICANCE STATEMENT: The study of proteins that are involved in cancer progression is important for developing targeted cancer therapies. Store-operated calcium entry-based proteins have been proposed as therapeutic cancer targets because inhibition of these proteins disrupts Ca²⁺ influx, thereby decreasing cell proliferation in certain cancers. Additionally, store-operated calcium entry-based proteins are implicated in many other disease states such as Stormorken syndrome, tubular aggregate myopathy, and immunodeficiency, highlighting the therapeutic relevance of these proteins.