IP3 Receptor Biology and Endoplasmic Reticulum Calcium Dynamics in Cancer

Abstract

Intracellular Ca 2+ signaling regulates a plethora of cellular functions. A central role in these processes is reserved for the inositol 1,4,5-trisphosphate receptor (IP 3 R), an ubiquitously expressed Ca 2+ -release channel, mainly located in the endoplasmic reticulum (ER). Three IP 3 R isoforms (IP 3 R1, IP 3 R2 and IP 3 R3) 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 IP 3 Rs in cell function, their dysregulation is linked to multiple pathologies. In this review, we highlight the complex role of the IP 3 R in cancer, as it participates in most of the socalled "hallmarks of cancer". In particular, the IP 3 R directly controls cell death and cell survival decisions via the regulation of autophagy and apoptosis. Moreover, the IP 3 R impacts cellular proliferation, migration and invasion. Typical examples of the role of the IP 3 Rs in these various processes are discussed. The relative levels of the IP 3 R 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 IP 3 R by tumor suppressors and oncogenes can be exploited to develop novel therapeutic approaches to fight cancer.

A non-canonical role for pyruvate kinase M2 as a functional modulator of Ca2+ signalling through IP3 receptors

“…Rather, the activity of IP 3 Rs represents the summative effects of various modifiers including accessory proteins, and factors such as ions, nucleotides, and redox status[1].The different modes of regulation of IP 3 R by accessory proteins provides the means to alterCa 2+ signals depending on cell type and physiological status. Significantly, there is a growing number of examples where the modulation of IP 3 R-mediated Ca 2+ signals by accessory proteins is hijacked by cancer cells to provide a survival or metastatic advantage[13,[45][46][47][48][49][50][51].The present work suggests that PKM2 may similarly provide an advantageous modulation of IP 3 R-mediated Ca 2+ signals in cancer. PKM2 is highly expressed in cancer cells, where in most cases its expression correlates with poor prognosis[52].…”

“…In conclusion, we propose that, in addition to downregulation of IP 3 R expression [63] signalling checkpoints, in a variety of disease states including cancer [13,16,[72][73][74][75].…”

“…Journal Pre-proof [13] from the ER lumen to the cytosol in the absence of any confounding sarco/endoplasmic reticulum Ca 2+ -ATPase, plasma-membrane Ca 2+ -ATPase or mitochondrial activity. The time course of the Ca 2+ flux experiment is illustrated in Figure 5B, where the fractional release of Ca 2+ from the ER (% efflux per 2-minute time window) is plotted as a function of time.…”

“…The sequestration of Ca 2+ by mitochondria stimulates respiration and biosynthetic processes, but it can also promote cell death [8]. Many cancer cells possess mechanisms to reduce IP 3 R-mediated cytosolic Ca 2+ signals and subsequent mitochondrial Ca 2+ uptake, thereby decreasing cell death susceptibility and thus acquiring a survival advantage [9][10][11][12][13].…”

Towards an integrative understanding of cancer mechanobiology: calcium, YAP, and microRNA under biophysical forces

“…153,203,204 IP 3 Rs have important roles in cancer by regulating cell autophagy, apoptosis, proliferation, migration, and invasion. 203,205,206…”