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From Orai to E-Cadherin: Subversion of Calcium Trafficking in Cancer to Drive Proliferation, Anoikis-Resistance, and Metastasis

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From Orai to E-Cadherin: Subversion of Calcium Trafficking in Cancer to Drive Proliferation, Anoikis-Resistance, and Metastasis biomedicines Review From Orai to E-Cadherin: Subversion of Calcium Trafficking in Cancer to Drive Proliferation, Anoikis-Resistance, and Metastasis Aarushi Sharma 1 and Randolph C. Elble 1,2,* 1 Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, IL 62702, USA; [email protected] 2 Department of Pharmacology and Simmons Cancer Institute, Southern Illinois University School of Medicine, Springfield, IL 62702, USA * Correspondence: [email protected]; Tel.: +217-545-7381 Received: 27 May 2020; Accepted: 19 June 2020; Published: 21 June 2020 Abstract: The common currency of epithelial differentiation and homeostasis is calcium, stored primarily in the endoplasmic reticulum, rationed according to need, and replenished from the extracellular milieu via store-operated calcium entry (SOCE). This currency is disbursed by the IP3 receptor in response to diverse extracellular signals. The rate of release is governed by regulators of proliferation, autophagy, survival, and programmed cell death, the strength of the signal leading to different outcomes. Intracellular calcium acts chiefly through intermediates such as calmodulin that regulates growth factor receptors such as epidermal growth factor receptor (EGFR), actin polymerization, and adherens junction assembly and maintenance. Here we review this machinery and its role in differentiation, then consider how cancer cells subvert it to license proliferation, resist anoikis, and enable metastasis, either by modulating the level of intracellular calcium or its downstream targets or effectors such as EGFR, E-cadherin, IQGAP1, TMEM16A, CLCA2, and TRPA1. Implications are considered for the roles of E-cadherin and growth factor receptors in circulating tumor cells and metastasis. The discovery of novel, cell type-specific modulators and effectors of calcium signaling offers new possibilities for cancer chemotherapy. Keywords: calcium; SOCE; SICE; IP3R; Orai; Stim; EGFR; E-cadherin; IQGAP; calmodulin; anoikis; circulating tumor cells 1. Introduction Calcium plays a unique role among all the ions that exist in the fluids in and around a living cell to maintain cellular homeostasis and other physiological functions [1]. Unlike sodium and potassium, calcium has a huge concentration gradient across cell membranes resulting from very low intracellular level of this cation [2]. All living cells maintain cytosolic calcium ion concentration in the range of 100 nM which is nearly 20,000-fold less than its extracellular level [3]. Early studies suggest this to be a mechanism adopted by cells to avoid stress by preventing precipitate formation with abundant phosphate anions that are required for energy production [3]. Consequently, most of the time low cytosolic calcium levels persist in cells which is leveraged in the form of small calcium ion fluxes creating greater cellular responses [2]. As a potent signaling agent, Ca2+ must also be sequestered from its targets in the cytosol before the time of action. This is accomplished by ATP-driven SERCA (Sarco/ER Ca2+- ATPase) pumps in the membrane of the ER, the principal repository of iCa2+ (intracellular calcium; Figure1)[4]. Release of Ca2+ from the ER is mediated by IP3 receptors, ligand-dependent Ca2+ channels that are regulated by a host of proteins in response to physiological cues [5,6]. Ca2+ may be released to the cytosol, Biomedicines 2020, 8, 169; doi:10.3390/biomedicines8060169 www.mdpi.com/journal/biomedicines BiomedicinesBiomedicines2020 2020, 8, 8 169, x FOR PEER REVIEW 2 of2 of 22 22 organelles such as the mitochondria, or to plasma membrane microdomains. Depletion of ER calcium to organelles such as the mitochondria, or to plasma membrane microdomains. Depletion of ER reserves is detected by a membrane sensor that responds by triggering the opening of a plasma calcium reserves is detected by a membrane sensor that responds by triggering the opening of a plasma membrane Ca2+ channel (Orai1) in a process termed store-operated calcium entry (SOCE) [7]. In the membrane Ca2+ channel (Orai1) in a process termed store-operated calcium entry (SOCE) [7]. In the first half of this review, we will describe how this machinery functions in normal epithelial cells and first half of this review, we will describe how this machinery functions in normal epithelial cells and how that changes in carcinomas, focusing on storage, utilization, and replenishment. In the latter half, how that changes in carcinomas, focusing on storage, utilization, and replenishment. In the latter half, we consider its role in epithelial proliferation, differentiation, and stress response, and how that is we consider its role in epithelial proliferation, differentiation, and stress response, and how that is exploited to promote metastasis. exploited to promote metastasis. FigureFigure 1. 1.Storage, Storage, utilization, utilization, and and renewal renewal of of intracellular intracellular calcium: calcium: a a simplified simplified view view of of core core Ca Ca2+ 2+ signalingsignaling machinery. machinery. CytosolicCytosolic CaCa22++ isis continuously continuously sequestered sequestered into into the the ER ER by by SERCA SERCA pumps. pumps. IP3 IP3signals signals from from certain certain cell cell-surface-surface receptors receptors (not (not shown) shown) opens opens IP3R IP3R channels channels that that direct direct Ca Ca2+ 2to+ tothe thecytosol cytosol or ormitochondrion. mitochondrion. Ca2+ Ca -binding2+ -binding proteins proteins in the in cyt theosol cytosol then then stimulate stimulate a host a hostof cell of celltype- type-dependentdependent signaling signaling pathways. pathways. In Insome some cell cell types, types, the the IP3R IP3R may co-existco-exist andand functionally functionally overlap overlap withwith another another channel, channel, the the ryanodine ryanodine receptor, receptor, RyR. RyR. Ca2+ Catransfer2+ transfer to mitochondrion to mitochondrion is mediated is mediated by IP3R by coupledIP3R coupled to the mitochondrial to the mitochondrial channel channel VDAC by VDAC the adapter by the moleculeadapter molecule GRP75. MCU GRP75 then. MCU admits then Ca admits2+ to theCa inner2+ to the matrix, inner where matrix, it drives where metabolism it drives metabolism and ATP production. and ATP production. Calcium overload Calcium causes overload apoptosis causes byapoptosis disrupting by membrane disrupting potential membrane and potential releasing and cytochrome releasing C; cytochrome thus, Ca2+ transfer C; thus, to Ca mitochondria2+ transfer to ismitochondria tightly modulated, is tightly either modulated, positively either or negatively, positively by or regulators negatively, of proliferation,by regulators autophagy, of proliferation, and deathautophagy, such as and the death Bcl-2 such family, as Beclin,the Bcl- AKT,2 family, PML, Beclin, p53, AKT, and BRCA1. PML, p53, Depletion and BRCA1. of ER Depletion Ca2+ causes of ER theCa Ca2+ causes2+ sensor the STIM1Ca2+ sensor to engage STIM1 the to plasmaengage membranethe plasma Camembrane2+ channel Ca Orai1,2+ channel causing Orai1, an causing influx of an 2+ extracellularinflux of extracellular Ca to the Ca cytosol.2+ to the SERCAcytosol. pumpsSERCA may pumps associate may associate with this with complex, this complex, allowing allowing more 2+ 2+ directmore replenishment direct replenishment of ER Ca of ER. TheCa2+ Golgi. The Golgi Ca pumpCa2+ pump SPCA2 SPCA2 can alsocan bindalso bind and activateand activate Orai1 Orai1 to driveto drive epithelial epitheli differentiation.al differentiation. See text forSee details. text for ER, endoplasmicdetails. ER, reticulum;endoplasmic MOM, reticulum; mitochondrial MOM, outermitochondrial membrane; outer MIM, membrane; mitochondrial MIM, mitochondrial inner membrane; inner MCU, membrane; mitochondrial MCU, mitochondrial calcium uniporter; calcium VDAC,uniporter; voltage-dependent VDAC, voltage anion-dependent channel. anion Black channel. arrows Black indicate arrows positive indicate regulation positive and regulation T-bar indicates and T- negativebar indicates regulation. negative Green regulation arrows. denote Green directionarrows denote of flow. direction of flow. 2. Storage and Management of Intracellular Calcium in Normal and Cancer cells 2.1. Intracellular Stores: IP3R, RyR, SERCA Biomedicines 2020, 8, 169 3 of 22 2. Storage and Management of Intracellular Calcium in Normal and Cancer Cells 2.1. Intracellular Stores: IP3R, RyR, SERCA Release of Ca2+ from the ER in epithelial cells is mediated primarily by a family of tetrameric channels termed inositol triphosphate receptors (IP3R 1 3) [5,6]. The IP3R opens in response to its − ligand IP3, generated by phospholipase C (PLC) in response to diverse extrinsic stimuli [5]. IP3Rs are also co-activated by Ca2+, creating a positive feedback loop when IP3 signaling is strong [5]. This stream of Ca2+ ions may be directed to the cytosol or to the mitochondria or other intracellular microdomains (Figure1). The IP3R is a tightly regulated rheostat and a signaling nexus. Ca2+ released from the ER is required for normal metabolism and proliferation, and its level determines whether cells divide or undergo autophagy or apoptosis [8–11]. Not surprisingly, many regulators of these processes bind and modulate the IP3R. AKT, a kinase that transduces mitogenic and survival signals, ensures a homeostatic level of activity by binding and phosphorylating IP3Rs at a conserved site, serine 2681 [12]. This modification dampens proapoptotic Ca2+ transfer to mitochondria and ensures cell
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