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Alterations of Calcium Homeostasis in Cancer Cells

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Alterations of Calcium Homeostasis in Cancer Cells Available online at www.sciencedirect.com ScienceDirect Alterations of calcium homeostasis in cancer cells Saverio Marchi and Paolo Pinton 2+ Typical hallmarks of cancer include programmed cell death These sources of Ca consist of a large number of 2+ 2+ evasion, uncontrolled cell growth, invasion, and metastasis. Ca pumps, channels, exchangers, and Ca -binding 2+ 2+ Changes in intracellular Ca levels can modulate signaling proteins that aim to control intracellular Ca levels 2+ pathways that control a broad range of cellular events, (Figure 1). Under resting conditions, [Ca ]c is main- including those important to tumorigenesis and cancer tained at a concentration of approximately 100 nM, 2+ progression. Here we discuss how known molecular mediators whereas extracellular [Ca ] is approximately 1 mM. 2+ 2+ of cellular Ca homeostasis impact tumor dynamics and how Ca entry is driven by the presence of a large electro- deregulation of major oncogenes and tumor suppressors is chemical gradient across the plasma membrane. Cells 2+ 2+ tightly associated with Ca signaling. manage this external pool of Ca by activating various Address entry channels with widely different properties. The voltage-gated calcium channels (VGCCs), which belong Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, Laboratory to the Cav family, are activated by depolarizing mem- for Technologies of Advanced Therapies (LTTA), University of Ferrara, brane potentials and are primarily expressed in excitable 44121 Ferrara, Italy 2+ cells. Otherwise, in non-excitable cells, Ca entry mostly occurs through non-voltage-gated channels. These in- Corresponding author: Pinton, Paolo ([email protected]) clude ligand-gated channels, such as the P2X purinergic ionotropic receptor families [2], and transient receptor Current Opinion in Pharmacology 2016, 29:1–6 potential (TRP) channels, which form a superfamily that This review comes from a themed issue on Cancer is divided into seven subfamily, the first of which is Edited by Francesco Di Virgilio and Paolo Pinton composed of the ‘canonical’ TRPs (TRPC subfamily) 2+ [3]. The main role of the TRP channels is to mediate Ca entry in response to various stimuli, including the pro- duction of diacylglycerol or stretching of the plasma http://dx.doi.org/10.1016/j.coph.2016.03.002 membrane. Nevertheless, some TRP channels can work 1471-4892/# 2016 Elsevier Ltd. All rights reserved. as store-operated channels. Indeed, when the ER releases 2+ its Ca content into the cytosol, a subsequent influx of 2+ extracellular Ca across membrane channels occurs, 2+ which sustains the Ca signal and enables the refilling of depleted stores, including the ER [4]. This event is 2+ termed SOCE (store-operated Ca entry) and is controlled Introduction at a molecular level by the canonical TRP channels, the 2+ In 1944, Carruthers and Suntzeff described for the first Ca release-activated calcium channel protein 1 (ORAI1) 2+ 2+ time a direct correlation between Ca and cancer, show- and the ER Ca sensors STIM1 (stromal interaction 2+ ing that a reduction in Ca levels in hyperplastic mouse molecule 1) and STIM2 [5]. ORAI1 and STIM1 physically epidermis was an important feature in precancerous con- interact at ER–plasma membrane junctions in a functional 2+ 2+ 2+ ditions [1]. More than 70 years later, the study of Ca Ca release-activated Ca (CRAC) channel complex dynamics in both carcinogenesis and tumor progression is through a dynamic interplay between their helices [6]. considered a key aspect of cancer biology. Spectacular 2+ advances in the understanding of intracellular Ca sig- ER calcium depletion originates following the binding of naling pathways have been made in recent years, leading physiological ligands to cell surface receptors that activate to the identification of important molecular players that phospholipase C to produce IP3 (inositol-1,4,5-trispho- are now the subjects of thorough mechanistic investiga- sphate), a second messenger that mediates the opening of 2+ tions. The remodeling of intracellular Ca homeostasis, IP3 receptors (IP3Rs) with a consequent rapid release of 2+ as a cause or consequence of the activity of different Ca into the cytoplasm. In mammals, different genes cancer-related proteins with altered functions, is now encode three isoforms of IP3R, termed IP3R type 1, 2 or thought of as a general hallmark of cancer cells. 3, which are highly similar in their primary sequences, but differ in terms of regulation [7]. A second family of ER 2+ Intracellular Ca signaling pathways channels, named ryanodine receptors (RyRs), is involved 2+ 2+ 2+ Increases in cytosolic Ca concentrations ([Ca ]c) occur in Ca release. This family contains three members with 2+ as a result of: firstly, Ca entry from the extracellular tissue-specific distributions. The mechanism of activation 2+ space and secondly, Ca release from intracellular stores, of each of these isoforms is different, ranging from pro- predominantly from the endoplasmic reticulum (ER). tein–protein interactions with plasma membrane VGCCs www.sciencedirect.com Current Opinion in Pharmacology 2016, 29:1–6 2 Cancer Figure 1 Extracellular Space (SOCE, membrane stretch, ligand 2+ P2X Basal [Ca ] = 1 mM AA, oxidative stress) (ATP) TRPCs TRPVs TRPMs VGCC receptor CICR Ca2+ 2+ ER RyR 2+ Ca Basal [Ca ] = 500 µM STIM2 Ca2+ STIM1 Ca2+ IP3R PMCA IP3 SERCA Ca2+ Cytosol Basal [Ca2+ ] = 100 nM Ca2+ VDAC STIM1 MCU SOCE mitochondrial matrix activation ORAI1 mitochondria Current Opinion in Pharmacology 2+ Intracellular Ca homeostasis. Various signaling molecules interact with receptors on the plasma membrane and elicit changes in the intracellular 2+ 2+ 2+ 2+ Ca concentration. Abbreviations: ER: endoplasmic reticulum; [Ca ]: calcium concentration; CICR Ca -induced Ca release; SOCE: store- 2+ operated Ca entry; ATP: adenosine triphosphate; AA: arachidonic acid; VGCC: voltage-gated calcium channel; TRP: transient receptor potential 2+ channel (C: canonical; V: vanilloid; M: melastatin); ORAI1: Ca release-activated calcium channel protein 1; STIM1: stromal interaction molecule 1; 2+ IP3: inositol-1,4,5-trisphosphate; IP3R: IP3 receptor; RyR: ryanodine receptor; SERCA: sarco/endoplasmic reticulum Ca -ATPase; MCU: 2+ mitochondrial calcium uniporter; VDAC: voltage-dependent anion channel; PMCA: plasma-membrane Ca -ATPase. 2+ 2+ to a particular phenomenon known as Ca -induced Ca presence of an electrochemical gradient (À180 mV) inside release (CICR) [8]. the mitochondrial matrix and the activity of a mitochon- drial calcium uniporter (MCU) complex [10 ]. In addition 2+ 2+ 2+ On the other hand, the sarco/endoplasmic reticulum Ca - to Ca buffering functions, mitochondrial Ca accumu- 2+ ATPase (SERCA) pumps catalyze Ca transport into the lation regulates metabolism and cell survival, and its im- lumen of the ER through an active process that requires plication in cancer is currently under investigation. Under a 2+ adenosine triphosphate (ATP). Thus, the SERCA system variety of stresses or types of damage, excessive Ca is 2+ refills the ER Ca content and simultaneously contributes released from the ER through the IP3Rs and transferred to 2+ 2+ to switching off of Ca signaling. Restoration of basal the mitochondria, leading to mitochondrial Ca overload, 2+ 2+ [Ca ]c also occurs via Ca extrusion through the plas- an opening of the mitochondrial permeability transition 2+ ma-membrane Ca -ATPase (PMCA) and the buffering pore [11,12] and the release of pro-apoptotic factors into the activity of the mitochondrial compartment [9 ]. Upon cytosol. 2+ discharge of ER Ca content, the mitochondria take up 2+ 2+ 2+ a large amount of Ca (10-fold higher than that measured Thus, both Ca influx and Ca liberation are controlled in the cytosol) due to their juxtaposition to the ER, the by a plethora of regulatory systems that provide spatial Current Opinion in Pharmacology 2016, 29:1–6 www.sciencedirect.com 2+ Ca signaling and cancer Marchi and Pinton 3 and temporal characteristics of an intracellular calcium decreased long-term survival in colorectal cancer [24], signal that are required for sustaining specific cellular as well as the dissemination of gastric cancers [25]. 2+ functions. How alterations of Ca homeostasis may im- However, IP3R3 has been demonstrated to be the pref- 2+ pact cancer development will be discussed in the next erential isoform that conveys apoptotic Ca signals to the section. mitochondria [26] and to contribute actively to cell death in a variety of tissues [27]. 2+ Ca players directly involved in cancer 2+ The contribution of Ca transporters and channels to Overall, these findings suggest a model depicting a multi- 2+ tumor development is especially evident in prostate cancer phasic Ca remodeling in tumor cells, in which increases 2+ (PCa), which is characterized by enhanced proliferation of [Ca ]c promote cell migration and represent an impor- and apoptosis resistance. Both TRPC6 and TRPV6 (TRP tant factor in the metastatic behavior of cancer cells, 2+ Vanilloid subfamily) display enhanced expression in PCa whereas reduced ER-mitochondria Ca transfer and/or and are associated with histological grade and Gleason attenuation of SOCE modulate cell death, thus actively 2+ score increases [13,14]. TRPV6 mediates Ca entry, which contributing to acquired resistance to apoptosis of primary is greatly increased in PCa due to a remodeling mechanism tumors. Notably, recent analyses of head and neck squa- involving the translocation of the TRPV6 channel
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