Journal article
Store-operated calcium entry-based targets for novel cancer therapeutic development
The Journal of pharmacology and experimental therapeutics, Vol.392(10), 103682
10/2025
DOI: 10.1016/j.jpet.2025.103682
PMCID: PMC13095634
PMID: 41033085
Abstract
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 which 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, or CRAC channel, that is critical for SOCE. Alternatively, adenylyl cyclase type 8 (AC8) binds to Orai1’s N-terminus causing Orai1 channel closing following phosphorylation by protein kinase (PKA). Other proteins also interact with Orai1 that influence the gating properties of this channel to elicit modulatory effects. As SOCE is critical for cellular Ca2+ balance and calcium-sensitive cellular functions, impairment of Orai1 function through 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 (TNBC) cells through mechanisms dependent on Ca2+ signaling. Thus, protein-protein interactions 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 TNBC. This review will examine Orai1 protein-protein interactions with STIM1 and AC8, discuss the relevance of these PPIs in cancer, and review the landscape of Orai1 inhibitors.
Details
- Title: Subtitle
- Store-operated calcium entry-based targets for novel cancer therapeutic development
- Creators
- Moana E. Hala’ufia - University of IowaDavid L. Roman - University of Iowa
- Resource Type
- Journal article
- Publication Details
- The Journal of pharmacology and experimental therapeutics, Vol.392(10), 103682
- DOI
- 10.1016/j.jpet.2025.103682
- PMID
- 41033085
- PMCID
- PMC13095634
- NLM abbreviation
- J Pharmacol Exp Ther
- ISSN
- 0022-3565
- eISSN
- 1521-0103
- Publisher
- ELSEVIER
- Grant note
- NIH National Cancer Institute: P30-CA086862 NIH National Institute of General Medical Sciences Pharmacological Sciences Training Grant: T32-GM067795 University of Iowa Lulu Merle Johnson Fellowship
This study was supported by a grant to the Holden Comprehensive Cancer Center (HCCC) from the NIH National Cancer Institute [Grant P30-CA086862] , the NIH National Institute of General Medical Sciences Pharmacological Sciences Training Grant [Grant T32-GM067795] , and the University of Iowa Lulu Merle Johnson Fellowship.
- Language
- English
- Electronic publication date
- 08/2025
- Date published
- 10/2025
- Academic Unit
- Pharmacy; Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Medicinal and Natural Products Chemistry
- Record Identifier
- 9984949226902771
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