Ca channel-forming ORAI proteins: cancer foes or cancer allies?

The ORAI family of ion channel-forming proteins in mammals includes three members, ORAI1, ORAI2 and ORAI3, encoded by homologous genes. Of these proteins the ORAI1 one received major attention as plasma membrane constituent of store-operated calcium entry (SOCE) in non-excitable cells. The functional significance of two other proteins, ORAI2 and ORAI3, is much less defined, although both of them participate to various extends in cell-specific modulation of SOCE as well as in supporting some of the store-independent calcium entry mechanisms. Calcium signaling becomes remodeled in cancer to promote cancer hallmarks - enhanced proliferation, resistance to apoptosis, motility and metastasizing. Although such remodeling commonly involves rearrangements of the whole molecular Ca-handling toolkit of the cell (Ca pumps and transporters, Ca-binding and storage proteins, Ca entry and release channels, Ca-dependent effectors), Ca entry through Orai-based channels is especially important, as its dysregulation may contribute to several cancer hallmarks. The latter depend on the type of Ca-permeable channel formed by ORAI-proteins, spatiotemporal characteristics of Ca signal that this channel contributes to, and the type Ca-dependent effector(s) targeted by this signal, all of which may be cancer-specific. By participating in global Ca entry, ORAI-based SOCE may also contribute to cytosolic Ca overload of cancer cells thereby playing pro-apoptotic, antineoplastic roles which can potentially be exploited for cancer treatment. This mini review examines various aspects of ORAI proteins in malignant transformation.