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

The calcium ion (Ca) 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 Ca transport systems. Inositol 1,4,5-trisphosphate (IP) receptors (IPRs) are IP-activated Ca release channels located on the endoplasmic reticulum (ER). They play pivotal roles in the regulation of cell death and survival by controlling Ca transfer from the ER to mitochondria through mitochondria-associated ER membranes (MAMs). Optimal levels of Ca mobilization to mitochondria are necessary for mitochondrial bioenergetics, whereas excessive Ca 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 IPRs to control Ca transfer into mitochondria. Another regulatory protein of IPR, IPR-binding protein released with IP (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 IPRs and regulation of Ca dynamics. The remodeling of Ca signaling by oncogenes and tumor suppressors that interact with IPRs has fundamental roles in the pathology of cancers.