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

Area of Science:

• Cellular Biology
• Biochemistry
• Molecular Medicine

Background:

• Store-operated calcium entry (SOCE) is crucial for cellular calcium homeostasis and replenishing endoplasmic reticulum Ca2+ stores.
• Orai1 is the primary calcium channel mediating SOCE, regulated by protein-protein interactions (PPIs) at its N- and C-termini.
• STIM1 activates Orai1, while AC8 inhibits it, highlighting the complex regulatory network of Orai1.

Purpose of the Study:

• To review Orai1 protein-protein interactions (PPIs) with STIM1 and AC8.
• To discuss the significance of these Orai1 PPIs in cancer progression, particularly triple-negative breast cancer.
• To explore Orai1 inhibitors as potential therapeutic targets for diseases linked to aberrant calcium signaling.

Main Methods:

• Literature review of Orai1 interactions and their roles in cellular functions and diseases.
• Analysis of the impact of Orai1 and AC8 overexpression on triple-negative breast cancer cell proliferation.
• Examination of existing Orai1 inhibitors and their therapeutic potential.

Main Results:

• Orai1 PPIs with STIM1 and AC8 are critical for regulating calcium influx and cellular functions.
• Aberrant Orai1 function and overexpression, particularly with AC8, promote triple-negative breast cancer cell proliferation via calcium signaling.
• Orai1 PPIs represent promising therapeutic targets for cancers and other diseases like Stormorken syndrome.

Conclusions:

• Targeting Orai1 PPIs offers a novel therapeutic strategy for diseases with dysregulated calcium signaling.
• Inhibition of Orai1-mediated calcium influx can reduce cancer cell proliferation.
• Orai1-based therapies hold promise for conditions lacking targeted treatments, including triple-negative breast cancer.