IP₃ Receptor Biology and Endoplasmic Reticulum Calcium Dynamics in Cancer

Intracellular Ca²⁺ signaling regulates a plethora of cellular functions. A central role in these processes is reserved for the inositol 1,4,5-trisphosphate receptor (IP₃R), a ubiquitously expressed Ca²⁺-release channel, mainly located in the endoplasmic reticulum (ER). Three IP₃R isoforms (IP₃R1, IP₃R2 and IP₃R3) exist, encoded respectively by ITPR1, ITPR2 and ITPR3. The proteins encoded by these genes are each about 2700 amino acids long and assemble into large tetrameric channels, which form the target of many regulatory proteins, including several tumor suppressors and oncogenes. Due to the important role of the IP₃Rs in cell function, their dysregulation is linked to multiple pathologies. In this review, we highlight the complex role of the IP₃R in cancer, as it participates in most of the so-called "hallmarks of cancer". In particular, the IP₃R directly controls cell death and cell survival decisions via regulation of autophagy and apoptosis. Moreover, the IP₃R impacts cellular proliferation, migration and invasion. Typical examples of the role of the IP₃Rs in these various processes are discussed. The relative levels of the IP₃R isoforms expressed and their subcellular localization, e.g. at the ER-mitochondrial interface, is hereby important. Finally, evidence is provided about how the knowledge of the regulation of the IP₃R by tumor suppressors and oncogenes can be exploited to develop novel therapeutic approaches to fight cancer.