Remodeling of Ca²⁺ signaling in cancer: Regulation of inositol 1,4,5-trisphosphate receptors through oncogenes and tumor suppressors

The calcium ion (Ca²⁺) is a ubiquitous intracellular signaling molecule that regulates diverse physiological and pathological processes, including cancer. Increasing evidence indicates that oncogenes and tumor suppressors regulate the Ca²⁺ transport systems. Inositol 1,4,5-trisphosphate (IP₃) receptors (IP₃Rs) are IP₃-activated Ca²⁺ release channels located on the endoplasmic reticulum (ER). They play pivotal roles in the regulation of cell death and survival by controlling Ca²⁺ transfer from the ER to mitochondria through mitochondria-associated ER membranes (MAMs). Optimal levels of Ca²⁺ mobilization to mitochondria are necessary for mitochondrial bioenergetics, whereas excessive Ca²⁺ flux into mitochondria causes loss of mitochondrial membrane integrity and apoptotic cell death. In addition to well-known functions on outer mitochondrial membranes, B-cell lymphoma 2 (Bcl-2) family proteins are localized on the ER and regulate IP₃Rs to control Ca²⁺ transfer into mitochondria. Another regulatory protein of IP₃R, IP₃R-binding protein released with IP₃ (IRBIT), cooperates with or counteracts the Bcl-2 family member depending on cellular states. Furthermore, several oncogenes and tumor suppressors, including Akt, K-Ras, phosphatase and tensin homolog (PTEN), promyelocytic leukemia protein (PML), BRCA1, and BRCA1 associated protein 1 (BAP1), are localized on the ER or at MAMs and negatively or positively regulate apoptotic cell death through interactions with IP₃Rs and regulation of Ca²⁺ dynamics. The remodeling of Ca²⁺ signaling by oncogenes and tumor suppressors that interact with IP₃Rs has fundamental roles in the pathology of cancers.