Orai3 calcium channel and ATP-binding cassette efflux transporters (ORAI3/ABC)

The Orai3 calcium channel and ATP-binding cassette (ABC) efflux transporter axis represents a complex signaling and transport system that mediates chemoresistance, particularly to cisplatin, in various cancers such as breast and lung carcinoma [Source: PubMed PMID: 31233811]. Orai3 is a store-operated calcium channel (SOCE) component that regulates the influx of extracellular calcium into the cytoplasm [Source: UniProt Q9BRQ5]. Elevated Orai3 activity leads to increased intracellular calcium levels, which in turn upregulates the expression and activity of ABC transporters like Multidrug Resistance Protein 1 (MDR1/ABCB1) and Multidrug Resistance-associated Protein 1 (MRP1/ABCC1) [Source: PubMed PMID: 26463143]. These transporters function as ATP-dependent pumps that actively extrude cisplatin from the cell, thereby reducing its DNA-damaging potential and allowing tumor cells to evade apoptosis. Pharmacological inhibition of Orai3 using small molecules like 2-APB or Synta66 has been shown to downregulate these transporters and restore cisplatin sensitivity in vitro. However, therapeutic targeting of this axis faces challenges due to the ubiquitous role of calcium signaling and the potential for systemic toxicity from broad ABC transporter inhibition. This interaction highlights the importance of ion channel-transporter crosstalk in the development of multidrug resistance (MDR) phenotypes.

Other names

Orai3-ABC transporter axisOrai3-mediated cisplatin resistance pathwayORAI3-ABCB1 interactionORAI3-ABCC1 interaction

Orai3-mediated calcium signaling regulates the expression and activity of ABC transporters, which facilitate the efflux of cisplatin from the intracellular environment, thereby reducing drug efficacy.