Orai channels in proliferation, invasion, and chemoresistance of tumor cells

Calcium signaling via store-operated calcium entry (SOCE) is critical for cellular functions implicated in cancer progression. Alterations in Orai channel isoforms, particularly Orai1 and Orai3, modulate SOCE and influence tumor cell proliferation, invasion, and survival. Here, we review and synthesize current evidence showing how Orai1 and Orai3 isoforms modulate oncogenic calcium signals through pathways such as phosphatidylinositol 3-kinase (PI3K)/Akt, ERK1/2, and NF-κB, contributing to tumor progression and chemoresistance by regulating apoptosis, autophagy, and oxidative stress responses. This isoform-specific remodeling enables tumor cells to adapt to therapeutic challenges and oxidative environments. Emerging data suggest that modulating Orai channel function and isoform composition may sensitize some cancer cells to apoptosis and attenuate invasive behavior, at least in specific experimental models. Taken together, available studies support a role for Orai channels as important regulators of tumor-associated Ca²⁺ signaling and highlight their potential as context-dependent targets to modulate survival and invasive behavior in cancer models.