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      • Record: found
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      Is Open Access

      Targeting calcium signaling in cancer therapy

      a , b , b , c , a , b , c , d , *

      Acta Pharmaceutica Sinica. B

      Elsevier

      20-GPPD, 20-O-β-D-glucopyranosyl-20(S)-protopanaxadiol, CaM, calmodulin, CaMKII, calmodulin-dependent protein kinase II, CBD, cannabidiol, CBG, cannabigerol, CPZ, capsazepine, CRAC, Ca2+ release-activated Ca2+ channel, CTL, cytotoxic T cells, CYP3A4, cytochrome P450 3A4, ER/SR, endoplasmic/sarcoplasmic reticulum, HCX, H+/Ca2+ exchangers, IP3, inositol 1,4,5-trisphosphate, IP3R (1, 2, 3), IP3 receptor (type 1, type 2, type 3), mAb, monoclonal antibody, MCU, mitochondrial Ca2+ uniporter, MCUR1, MCU uniporter regulator 1, MICU (1, 2, 3), mitochondrial calcium uptake (type 1, type 2, type 3), MLCK, myosin light-chain kinase, NCX, Na+/Ca2+ exchanger, NFAT, nuclear factor of activated T cells, NF-κB, nuclear factor-κB, NSCLC, non-small cell lung cancer, OSCC, oral squamous cell carcinoma cells, PKC, protein kinase C, PM, plasma membrane, PMCA, plasma membrane Ca2+-ATPase, PTP, permeability transition pore, ROS, reactive oxygen species, RyR, ryanodine receptor, SERCA, SR/ER Ca2+-ATPase, SOCE, store-operated Ca2+ entry, SPCA, secretory pathway Ca2+-ATPase, TEA, tetraethylammonium, TG, thapsigargin, TPC2, two-pore channel 2, TRIM, 1-(2-(trifluoromethyl) phenyl) imidazole, TRP (A, C, M, ML, N, P, V), transient receptor potential (ankyrin, canonical, melastatin, mucolipin, no mechanoreceptor potential C, polycystic, vanilloid) , VGCC, voltage-gated Ca2+ channel, Ca2+ channels, Store-operated Ca2+ entry, Cell proliferation, Migration, Apoptosis, Channel blockers;, Cancer therapy

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          Abstract

          The intracellular calcium ions (Ca 2+) act as second messenger to regulate gene transcription, cell proliferation, migration and death. Accumulating evidences have demonstrated that intracellular Ca 2+ homeostasis is altered in cancer cells and the alteration is involved in tumor initiation, angiogenesis, progression and metastasis. Targeting derailed Ca 2+ signaling for cancer therapy has become an emerging research area. This review summarizes some important Ca 2+ channels, transporters and Ca 2+-ATPases, which have been reported to be altered in human cancer patients. It discusses the current research effort toward evaluation of the blockers, inhibitors or regulators for Ca 2+ channels/transporters or Ca 2+-ATPase pumps as anti-cancer drugs. This review is also aimed to stimulate interest in, and support for research into the understanding of cellular mechanisms underlying the regulation of Ca 2+ signaling in different cancer cells, and to search for novel therapies to cure these malignancies by targeting Ca 2+ channels or transporters.

          Graphical abstract

          Ca 2+ plays vital roles in normal cell physiology, such as gene transcription, cell proliferation and migration. Abnormal Ca 2+ signaling by virtue of altered channel expression or activation contributes to carcinogenesis and promotes tumor development. Targeting the dysregulated Ca 2+ channels/transporters/pumps may provide a promising chemotherapy for cancer treatment.

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          Most cited references 188

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          Calcium oscillations increase the efficiency and specificity of gene expression.

          Cytosolic calcium ([Ca2+]i) oscillations are a nearly universal mode of signalling in excitable and non-excitable cells. Although Ca2+ is known to mediate a diverse array of cell functions, it is not known whether oscillations contribute to the efficiency or specificity of signalling or are merely an inevitable consequence of the feedback control of [Ca2+]i. We have developed a Ca2+ clamp technique to investigate the roles of oscillation amplitude and frequency in regulating gene expression driven by the proinflammatory transcription factors NF-AT, Oct/OAP and NF-kappaB. Here we report that oscillations reduce the effective Ca2+ threshold for activating transcription factors, thereby increasing signal detection at low levels of stimulation. In addition, specificity is encoded by the oscillation frequency: rapid oscillations stimulate all three transcription factors, whereas infrequent oscillations activate only NF-kappaB. The genes encoding the cytokines interleukin (IL)-2 and IL-8 are also frequency-sensitive in a way that reflects their degree of dependence on NF-AT versus NF-kappaB. Our results provide direct evidence that [Ca2+]i oscillations increase both the efficacy and the information content of Ca2+ signals that lead to gene expression and cell differentiation.
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            Orai1 and STIM1 are critical for breast tumor cell migration and metastasis.

            Tumor metastasis is the primary cause of death of cancer patients. Understanding the molecular mechanisms underlying tumor metastasis will provide potential drug targets. We report here that Orai1 and STIM1, both of which are involved in store-operated calcium entry, are essential for breast tumor cell migration in vitro and tumor metastasis in mice. Reduction of Orai1 or STIM1 by RNA interference in highly metastatic human breast cancer cells or treatment with a pharmacological inhibitor of store-operated calcium channels decreased tumor metastasis in animal models. Our data demonstrate a role for Orai1 and STIM1 in tumor metastasis and suggest store-operated calcium entry channels as potential cancer therapeutic targets.
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              Imaging interorganelle contacts and local calcium dynamics at the ER-mitochondrial interface.

              The ER-mitochondrial junction provides a local calcium signaling domain that is critical for both matching energy production with demand and the control of apoptosis. Here, we visualize ER-mitochondrial contact sites and monitor the localized [Ca(2+)] changes ([Ca(2+)](ER-mt)) using drug-inducible fluorescent interorganelle linkers. We show that all mitochondria have contacts with the ER, but plasma membrane (PM)-mitochondrial contacts are less frequent because of interleaving ER stacks in both RBL-2H3 and H9c2 cells. Single mitochondria display discrete patches of ER contacts and show heterogeneity in the ER-mitochondrial Ca(2+) transfer. Pericam-tagged linkers revealed IP(3)-induced [Ca(2+)](ER-mt) signals that exceeded 9 microM and endured buffering bulk cytoplasmic [Ca(2+)] increases. Altering linker length to modify the space available for the Ca(2+) transfer machinery had a biphasic effect on [Ca(2+)](ER-mt) signals. These studies provide direct evidence for the existence of high-Ca(2+) microdomains between the ER and mitochondria and suggest an optimal gap width for efficient Ca(2+) transfer. 2010 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Acta Pharm Sin B
                Acta Pharm Sin B
                Acta Pharmaceutica Sinica. B
                Elsevier
                2211-3835
                2211-3843
                13 December 2016
                January 2017
                13 December 2016
                : 7
                : 1
                : 3-17
                Affiliations
                [a ]State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
                [b ]Department of Surgery, Division of Thoracic Surgery, The Ohio State University, Columbus, OH 43210, USA
                [c ]Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA
                [d ]College of Nursing and Health Innovation, The University of Texas at Arlington, Arlington, TX 76019, USA
                Author notes
                [* ]Corresponding author at: College of Nursing and Health Innovation, The University of Texas at Arlington, LS Building 239, 501 S. Nedderman Dr., Arlington, TX 76019, USA. Tel.: +1 817 272 2261. zui.pan@ 123456uta.edu
                Article
                S2211-3835(16)30175-7
                10.1016/j.apsb.2016.11.001
                5237760
                © 2017 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                Categories
                Review

                cam, calmodulin, camkii, calmodulin-dependent protein kinase ii, cbd, cannabidiol, cbg, cannabigerol, cpz, capsazepine, crac, ca2+ release-activated ca2+ channel, ctl, cytotoxic t cells, cyp3a4, cytochrome p450 3a4, er/sr, endoplasmic/sarcoplasmic reticulum, hcx, h+/ca2+ exchangers, ip3, inositol 1,4,5-trisphosphate, ip3r (1, 2, 3), ip3 receptor (type 1, type 2, type 3), mab, monoclonal antibody, mcu, mitochondrial ca2+ uniporter, mcur1, mcu uniporter regulator 1, micu (1, 2, 3), mitochondrial calcium uptake (type 1, type 2, type 3), mlck, myosin light-chain kinase, ncx, na+/ca2+ exchanger, nfat, nuclear factor of activated t cells, nf-κb, nuclear factor-κb, nsclc, non-small cell lung cancer, oscc, oral squamous cell carcinoma cells, cancer therapy, pkc, protein kinase c, pm, plasma membrane, pmca, plasma membrane ca2+-atpase, ptp, permeability transition pore, ros, reactive oxygen species, ryr, ryanodine receptor, serca, sr/er ca2+-atpase, soce, store-operated ca2+ entry, spca, secretory pathway ca2+-atpase, tea, tetraethylammonium, tg, thapsigargin, tpc2, two-pore channel 2, trim, 1-(2-(trifluoromethyl) phenyl) imidazole, trp (a, c, m, ml, n, p, v), transient receptor potential (ankyrin, canonical, melastatin, mucolipin, no mechanoreceptor potential c, polycystic, vanilloid), vgcc, voltage-gated ca2+ channel, ca2+ channels, store-operated ca2+ entry, cell proliferation, migration, apoptosis, channel blockers;, 20-gppd, 20-o-β-d-glucopyranosyl-20(s)-protopanaxadiol

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