Type 3 IP 3 receptors: The chameleon in cancer.

Inositol 1,4,5-trisphosphate (IP) receptors (IPRs), intracellular calcium (Ca) release channels, fulfill key functions in cell death and survival processes, whose dysregulation contributes to oncogenesis. This is essentially due to the presence of IPRs in microdomains of the endoplasmic reticulum (ER) in close proximity to the mitochondria. As such, IPRs enable efficient Ca transfers from the ER to the mitochondria, thus regulating metabolism and cell fate. This review focuses on one of the three IPR isoforms, the type 3 IPR (IPR3), which is linked to proapoptotic ER-mitochondrial Ca transfers. Alterations in IPR3 expression have been highlighted in numerous cancer types, leading to dysregulations of Ca signaling and cellular functions. However, the outcome of IPR3-mediated Ca transfers for mitochondrial function is complex with opposing effects on oncogenesis. IPR3 can either suppress cancer by promoting cell death and cellular senescence or support cancer by driving metabolism, anabolic processes, cell cycle progression, proliferation and invasion. The aim of this review is to provide an overview of IPR3 dysregulations in cancer and describe how such dysregulations alter critical cellular processes such as proliferation or cell death and survival. Here, we pose that the IPR3 isoform is not only linked to proapoptotic ER-mitochondrial Ca transfers but might also be involved in prosurvival signaling.