Tumor suppressive Ca2+ signaling is driven by IP3 receptor fitness

Abstract

Intracellular Ca2+ signals critically control a plethora of cellular functions, of which many impact cellular death and/or survival, processes often dysregulated in cancer [1]. In healthy cells, Ca 2+ signaling is employed for normal cell physiology and survival functions [2]. Yet, when a cell is exposed to toxic stimuli or suffering from enduring cell stress, like irreparable DNA damage, the Ca 2+ -signaling toolbox can be rapidly switched from a "pro-survival" modus into a "pro-death" modus, thereby initiating demise pathways [3]. The highly dynamic nature of Ca 2+ signaling allows cells to swiftly response to stress and damage, preventing the survival of damaged cells and malignant transformation that eventually results in tumor formation. Alterations in the expression, activity and regulation of Ca 2+ -transport systems both at the plasma membrane and at organelles like the endoplasmic reticulum (ER) and mitochondria have been implicated in oncogenesis and neoplasia [1,4]. These changes result in aberrant Ca 2+ -signaling events that could favor resistance to cell death, migration or senescence escape [5].Over the last decade, we learnt that tight contacts and functional connections involving Ca 2+ exchanges between the ER, the main intracellular Ca 2+ -storage organelle, and the mitochondria are pivotal for cell-fate decisions [3,[6][7][8].These contact sites contain chaperone-coupled Ca 2+ -flux systems: the IP 3 receptors (IP 3 Rs) at the ER side and the voltage-dependent anion channels (VDACs) at the mitochondrial outer membrane side [9]. These are controlled/exploited by several cellular factors and regulatory proteins, including oncogenes and tumor suppressors [10][11][12]. Basal Ca 2+ fluxes between ER and mitochondria sustain anabolic pathways for mitochondrial metabolism, ensuring proper cell cycle progression [13]. Yet, continued elevated ER-mitochondrial Ca 2+ transfers result in loss of mitochondrial membrane integrity and release of apoptogenic factors [14]. Tuned ER-mitochondrial Ca 2+ transfer is therefore key to cells' response to pro-apoptotic stimuli: the failure of which results in cell death resistance, as often observed in cancer cells [15,16]. In fact, the efficacy of chemotherapeutic agents and photodynamic therapy depends on the ability of these agents to elicit ER-mitochondrial Ca 2+ exchanges [15]. In the context of apoptosis, previous work proposed unique roles for the type 3 IP 3 R isoform (IP 3 R3) [17] and type 1 VDAC isoform (VDAC1) [18] even though other IP 3 R isoforms can contribute to the initiation of cell death programs [19,20]. Received: 12.10.2017, Accepted 20.10.2017, Published 01.11.2017. Keywords: cancer, oncogenesis, tumor suppression, IP3R3, calcium signaling, PTEN, FBXL2, BAP1. G. Bultynck and M. Campanella (2017 . Several tumor suppressors and oncogenes have been identified as direct regulators of the IP 3 R, whereby tumor suppressors (like BRCA1, PTEN, PML) and oncogenes (like Bcl-2, PKB/Akt) that respectively promote and suppress the activity of IP 3 R cha...

Editorial: Inter-Organelle Calcium Communication in Cancer

“…This versatility is achieved by the interplay of the Ca 2+ -signaling toolkit (including channels, pumps, exchangers, and binding/buffering proteins), generating specific spatiotemporal Ca 2+ signals ( 14 ). Alterations in the expression and/or function of these Ca 2+ -transport/binding systems have been implicated in oncogenesis and cancer progression ( 15 , 16 ). In this regard, contribute a comprehensive review focused on the generation, regulation, and function of Ca 2+ microdomains in T lymphocytes.…”

Modulation of IP3 Receptor Stability and Its Implication in Cell Death and Disease

“…Recently, F-box protein FBXL2, one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), was identified to bind to and ubiquitinate IP3R3, thereby targeting it for proteasomal degradation (Bultynck and Campanella, 2017;Kuchay et al, 2017).…”

“…These proteins exert precise control of the Ca 2+ flux from the ER to the mitochondria either directly by interacting with IP3R or indirectly by interacting with other Ca 2+ -transport systems, thereby affecting steady state ER Ca 2+ loading (Akl and Bultynck, 2013;Bittremieux et al, 2016). IP3R3 is the isoform that is most abundant at the MAMs and as such it is an important target for regulating the Ca 2+ release in these microdomains (Bultynck and Campanella, 2017;De Stefani et al, 2012;Marchi et al, 2017b;Pedriali et al, 2017).…”

Biological Regulatory Network (BRN) Analysis and Molecular Docking Simulations to Probe the Modulation of IP3R Mediated Ca2+ Signaling in Cancer

“…Subsequently, IP 3 binds to its receptor (IP 3 R) present on the endoplasmic reticulum [ 13 ] where a low level of IP 3 is responsible for IP 3 R channel activation in basal conditions. Additionally, several oncogenes and tumor suppressors (such as B-cell lymphoma 2 (Bcl-2) family proteins [ 14 , 15 ], IP 3 R-binding proteins [ 16 ], phosphatase and tensin homolog (PTEN) [ 17 , 18 , 19 ] and BRCA1 associated protein 1 (BAP1) [ 20 , 21 ]) directly bind with IP 3 Rs and modulate their activity to control Ca 2+ influx into mitochondria. Under various pathophysiological conditions, changes in the expression level of these binding factors may alter the activation of IP 3 R, consequently affecting the mitochondrial Ca 2+ concentration level followed by uncontrolled cell growth or cell death [ 16 , 21 ].…”