Altered expression of stromal interaction molecule (STIM)-calcium release-activated calcium channel protein (ORAI) and inositol 1,4,5-trisphosphate receptors (IP(3)Rs) in cancer: will they become a new battlefield for oncotherapy?

The stromal interaction molecule (STIM)-calcium release-activated calcium channel protein (ORAI) and inositol 1,4,5-trisphosphate receptors (IP(3)Rs) play pivotal roles in the modulation of Ca(2+)-regulated pathways from gene transcription to cell apoptosis by driving calcium-dependent signaling processes. Increasing evidence has implicated the dysregulation of STIM–ORAI and IP(3)Rs in tumorigenesis and tumor progression. By controlling the activities, structure, and/or expression levels of these Ca(2+)-transporting proteins, malignant cancer cells can hijack them to drive essential biological functions for tumor development. However, the molecular mechanisms underlying the participation of STIM–ORAI and IP(3)Rs in the biological behavior of cancer remain elusive. In this review, we summarize recent advances regarding STIM–ORAI and IP(3)Rs and discuss how they promote cell proliferation, apoptosis evasion, and cell migration through temporal and spatial rearrangements in certain types of malignant cells. An understanding of the essential roles of STIM–ORAI and IP(3)Rs may provide new pharmacologic targets that achieve a better therapeutic effect by inhibiting their actions in key intracellular signaling pathways.