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ScienceDirect
Alterations of calcium homeostasis in cancer cells
Saverio Marchi and Paolo Pinton
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Typical hallmarks of cancer include programmed cell death These sources of Ca consist of a large number of
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evasion, uncontrolled cell growth, invasion, and metastasis. Ca pumps, channels, exchangers, and Ca -binding
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Changes in intracellular Ca levels can modulate signaling proteins that aim to control intracellular Ca levels
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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,
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progression. Here we discuss how known molecular mediators whereas extracellular [Ca ] is approximately 1 mM.
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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
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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)
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[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
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its Ca content into the cytosol, a subsequent influx of
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extracellular Ca across membrane channels occurs,
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which sustains the Ca signal and enables the refilling
of depleted stores, including the ER [4]. This event is
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termed SOCE (store-operated Ca entry) and is controlled
Introduction at a molecular level by the canonical TRP channels, the
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In 1944, Carruthers and Suntzeff described for the first Ca release-activated calcium channel protein 1 (ORAI1)
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time a direct correlation between Ca and cancer, show- and the ER Ca sensors STIM1 (stromal interaction
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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
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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
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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
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tions. The remodeling of intracellular Ca homeostasis, IP3 receptors (IP3Rs) with a consequent rapid release of
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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
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Intracellular Ca signaling pathways channels, named ryanodine receptors (RyRs), is involved
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Increases in cytosolic Ca concentrations ([Ca ]c) occur in Ca release. This family contains three members with
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as a result of: firstly, Ca entry from the extracellular tissue-specific distributions. The mechanism of activation
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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
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Intracellular Ca homeostasis. Various signaling molecules interact with receptors on the plasma membrane and elicit changes in the intracellular
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Ca concentration. Abbreviations: ER: endoplasmic reticulum; [Ca ]: calcium concentration; CICR Ca -induced Ca release; SOCE: store-
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operated Ca entry; ATP: adenosine triphosphate; AA: arachidonic acid; VGCC: voltage-gated calcium channel; TRP: transient receptor potential
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channel (C: canonical; V: vanilloid; M: melastatin); ORAI1: Ca release-activated calcium channel protein 1; STIM1: stromal interaction molecule 1;
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IP3: inositol-1,4,5-trisphosphate; IP3R: IP3 receptor; RyR: ryanodine receptor; SERCA: sarco/endoplasmic reticulum Ca -ATPase; MCU:
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mitochondrial calcium uniporter; VDAC: voltage-dependent anion channel; PMCA: plasma-membrane Ca -ATPase.
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to a particular phenomenon known as Ca -induced Ca presence of an electrochemical gradient ( 180 mV) inside
release (CICR) [8]. the mitochondrial matrix and the activity of a mitochon-