Abstract
Store-operated Ca2+ entry (SOCE) controls intracellular Ca2+ homeostasis and regulates a wide range of cellular events including proliferation, migration and invasion. The discovery of STIM proteins as Ca2+ sensors and Orai proteins as Ca2+ channel pore forming units provided molecular tools to understand the physiological function of SOCE. Many studies have revealed the pathophysiological roles of Orai and STIM in tumor cells. This review focuses on recent advances in SOCE and its contribution to tumorigenesis. Altered Orai and/or STIM functions may serve as biomarkers for cancer prognosis, and targeting the SOCE pathway may provide a novel means for cancer treatment.
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Berridge MJ, Bootman MD, Roderick HL. Calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol, 2003, 4: 517–529
Berridge MJ, Lipp P, Bootman MD. The versatility and universality of calcium signalling. Nat Rev Mol Cell Biol, 2000, 1: 11–21
Hajnoczky G, Davies E, Madesh M. Calcium signaling and apoptosis. Biochem Biophys Res Commun, 2003, 304: 445–454
Lipskaia L, Lompre AM. Alteration in temporal kinetics of Ca2+ signaling and control of growth and proliferation. Biol Cell, 2004, 96: 55–68
Rizzuto R, Pinton P, Ferrari D, Chami M, Szabadkai G, Magalhaes PJ, Di Virgilio F, Pozzan T. Calcium and apoptosis: facts and hypotheses. Oncogene, 2003, 22: 8619–8627
Bell N, Hann V, Redfern CP, Cheek TR. Store-operated Ca(2+) entry in proliferating and retinoic acid-differentiated N- and S-type neuroblastoma cells. Biochim Biophys Acta, 2013, 1833: 643–651
Bergmeier W, Weidinger C, Zee I, Feske S. Emerging roles of store-operated Ca(2+) entry through stim and orai proteins in immunity, hemostasis and cancer. Channels (Austin), 2013, 7: 379–391
Barr VA, Bernot KM, Srikanth S, Gwack Y, Balagopalan L, Regan CK, Helman DJ, Sommers CL, Oh-Hora M, Rao A, Samelson LE. Dynamic movement of the calcium sensor STIM1 and the calcium channel Orai1 in activated T-cells: puncta and distal caps. Mol Biol Cell, 2008, 19: 2802–2817
Chen YF, Chiu WT, Chen YT, Lin PY, Huang HJ, Chou CY, Chang HC, Tang MJ, Shen MR. Calcium store sensor stromal-interaction molecule 1-dependent signaling plays an important role in cervical cancer growth, migration, and angiogenesis. Proc Natl Acad Sci USA, 2011, 108: 15225–15230
Chen YT, Chen YF, Chiu WT, Liu KY, Liu YL, Chang JY, Chang HC, Shen MR. Microtubule-associated histone deacetylase 6 supports the calcium store sensor STIM1 in mediating malignant cell behaviors. Cancer Res, 2013, 73: 4500–4509
Feng M, Grice DM, Faddy HM, Nguyen N, Leitch S, Wang Y, Muend S, Kenny PA, Sukumar S, Roberts-Thomson SJ, Monteith GR, Rao R. Store-independent activation of Orai1 by SPCA2 in mammary tumors. Cell, 2010, 143: 84–98
Motiani RK, Hyzinski-Garcia MC, Zhang X, Henkel MM, Abdullaev IF, Kuo YH, Matrougui K, Mongin AA, Trebak M. STIM1 and Orai1 mediate CRAC channel activity and are essential for human glioblastoma invasion. Pflugers Arch, 2013, 465: 1249–1260
Srikanth S, Gwack Y. Orai1-NFAT signalling pathway triggered by T cell receptor stimulation. Mol Cells, 2013, 35: 182–194
Yang N, Tang Y, Wang F, Zhang H, Xu D, Shen Y, Sun S, Yang G. Blockade of store-operated Ca(2+) entry inhibits hepatocarcinoma cell migration and invasion by regulating focal adhesion turnover. Cancer Lett, 2013, 330: 163–169
Yang S, Zhang JJ, Huang XY. Orai1 and STIM1 are critical for breast tumor cell migration and metastasis. Cancer Cell, 2009, 15: 124–134
Lewis RS. Calcium oscillations in T-cells: mechanisms and consequences for gene expression. Biochem Soc Trans, 2003, 31: 925–929
Giannone G, Ronde P, Gaire M, Haiech J, Takeda K. Calcium oscillations trigger focal adhesion disassembly in human U87 astrocytoma cells. J Biol Chem, 2002, 277: 26364–26371
Ronde P, Giannone G, Gerasymova I, Stoeckel H, Takeda K, Haiech J. Mechanism of calcium oscillations in migrating human astrocytoma cells. Biochim Biophys Acta, 2000, 1498: 273–280
Parekh AB, Putney JW Jr. Store-operated calcium channels. Physiol Rev, 2005, 85: 757–810
Putney JW Jr. A model for receptor-regulated calcium entry. Cell Calcium, 1986, 7: 1–12
Mercer JC, Dehaven WI, Smyth JT, Wedel B, Boyles RR, Bird GS, Putney JW Jr. Large store-operated calcium selective currents due to co-expression of Orai1 or Orai2 with the intracellular calcium sensor, STIM1. J Biol Chem, 2006, 281: 24979–24990
Moreau B, Straube S, Fisher RJ, Putney JW Jr., Parekh AB. Ca2+-calmodulin-dependent facilitation and Ca2+ inactivation of Ca2+ release-activated Ca2+ channels. J Biol Chem, 2005, 280: 8776–8783
Putney JWJ, Broad LM, Braun FJ, Lievremont JP, Bird GS. Mechanisms of capacitative calcium entry. J Cell Sci, 2001, 114: 2223–2229
Wedel B, Boyles RR, Putney JW, Bird GS. Role of the store-operated calcium entry proteins, STIM1 and Orai1, in muscarinic-cholinergic receptor stimulated calcium oscillations in human embryonic kidney cells. J Physiol, 2007, 579: 679–689
Hoth M, Penner R. Depletion of intracellular calcium stores activates a calcium current in mast cells. Nature, 1992, 355: 353–356
Zhang SL, Yu Y, Roos J, Kozak JA, Deerinck TJ, Ellisman MH, Stauderman KA, Cahalan MD. STIM1 is a Ca2+ sensor that activates crac channels and migrates from the Ca2+ store to the plasma membrane. Nature, 2005, 437: 902–905
Liou J, Kim ML, Heo WD, Jones JT, Myers JW, Ferrell JE Jr., Meyer T. STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx. Curr Biol, 2005, 15: 1235–1241
Roos J, DiGregorio PJ, Yeromin AV, Ohlsen K, Lioudyno M, Zhang S, Safrina O, Kozak JA, Wagner SL, Cahalan MD, Velicelebi G, Stauderman KA. STIM1, an essential and conserved component of store-operated Ca2+ channel function. J Cell Biol, 2005, 169: 435–445
Yeromin AV, Zhang SL, Jiang W, Yu Y, Safrina O, Cahalan MD. Molecular identification of the CRAC channel by altered ion selectivity in a mutant of Orai. Nature, 2006, 443: 226–229
Prakriya M, Feske S, Gwack Y, Srikanth S, Rao A, Hogan PG. Orai1 is an essential pore subunit of the CRAC channel. Nature, 2006, 443: 230–233
Vig M, Peinelt C, Beck A, Koomoa DL, Rabah D, Koblan-Huberson M, Kraft S, Turner H, Fleig A, Penner R, Kinet JP. CRACM1 is a plasma membrane protein essential for store-operated Ca2+ entry. Science, 2006, 312: 1220–1223
Feske S, Gwack Y, Prakriya M, Srikanth S, Puppel SH, Tanasa B, Hogan PG, Lewis RS, Daly M, Rao A. A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function. Nature, 2006, 441: 179–185
Luik RM, Wu MM, Buchanan J, Lewis RS. The elementary unit of store-operated Ca2+ entry: local activation of CRAC channels by STIM1 at ER-plasma membrane junctions. J Cell Biol, 2006, 174: 815–825
Wu MM, Buchanan J, Luik RM, Lewis RS. Ca2+ store depletion causes STIM1 to accumulate in ER regions closely associated with the plasma membrane. J Cell Biol, 2006, 174: 803–813
Ong HL, Cheng KT, Liu X, Bandyopadhyay BC, Paria BC, Soboloff J, Pani B, Gwack Y, Srikanth S, Singh BB, Gill D, Ambudkar IS. Dynamic assembly of TRPC1/STIM1/Orai1 ternary complex is involved in store operated calcium influx: evidence for similarities in SOC and CRAC channel components. J Biol Chem, 2007, 282: 9105–9116
Vig M, Beck A, Billingsley JM, Lis A, Parvez S, Peinelt C, Koomoa DL, Soboloff J, Gill DL, Fleig A, Kinet JP, Penner R. CRACM1 multimers form the ion-selective pore of the CRAC channel. Curr Biol, 2006, 16: 2073–2079
Soboloff J, Spassova MA, Hewavitharana T, He LP, Xu W, Johnstone LS, Dziadek MA, Gill DL. STIM2 is an inhibitor of STIM1-mediated store-operated Ca2+ entry. Curr Biol, 2006, 16: 1465–1470
Soboloff J, Spassova MA, Tang XD, Hewavitharana T, Xu W, Gill DL. Orai1 and STIM reconstitute store-operated calcium channel function. J Biol Chem, 2006, 281: 20661–20665
Spassova MA, Soboloff J, He LP, Xu W, Dziadek MA, Gill DL. STIM1 has a plasma membrane role in the activation of store-operated Ca(2+) channels. Proc Natl Acad Sci USA, 2006, 103: 4040–4045
Huang GN, Zeng W, Kim JY, Yuan JP, Han L, Muallem S, Worley PF. STIM1 carboxyl-terminus activates native SOC, I(crac) and TRPC1 channels. Nat Cell Biol, 2006, 8: 1003–1010
Ma J, Pan Z. Retrograde activation of store-operated calcium channel. Cell Calcium, 2003, 33: 375–384
Patton AM, Kassis J, Doong H, Kohn EC. Calcium as a molecular target in angiogenesis. Curr Pharm Des, 2003, 9: 543–551
Guo L, Li ZS, Wang HL, Ye CY, Zhang DC. Carboxyamido-triazole inhibits proliferation of human breast cancer cells via G(2)/M cell cycle arrest and apoptosis. Eur J Pharmacol, 2006, 538: 15–22
Perabo FG, Demant AW, Wirger A, Schmidt DH, Sitia M, Wardelmann E, Muller SC, Kohn EC. Carboxyamido-triazole (CAI) reverses the balance between proliferation and apoptosis in a rat bladder cancer model. Anticancer Res, 2005, 25: 725–729
Ge S, Rempel SA, Divine G, Mikkelsen T. Carboxyamido-triazole induces apoptosis in bovine aortic endothelial and human glioma cells. Clin Cancer Res, 2000, 6: 1248–1254
Mignen O, Brink C, Enfissi A, Nadkarni A, Shuttleworth TJ, Giovannucci DR, Capiod T. Carboxyamidotriazole-induced inhibition of mitochondrial calcium import blocks capacitative calcium entry and cell proliferation in HEK-293 cells. J Cell Sci, 2005, 118: 5615–5623
Enfissi A, Prigent S, Colosetti P, Capiod T. The blocking of capacitative calcium entry by 2-aminoethyl diphenylborate (2-APB) and carboxyamidotriazole (CAI) inhibits proliferation in Hep G2 and Huh-7 human hepatoma cells. Cell calcium, 2004, 36: 459–467
Padar S, Bose DD, Livesey JC, Thomas DW. 2-aminoethoxydiphenyl borate perturbs hormone-sensitive calcium stores and blocks store-operated calcium influx pathways independent of cytoskeletal disruption in human A549 lung cancer cells. Biochem Pharmacol, 2005, 69: 1177–1186
Kazerounian S, Pitari GM, Shah FJ, Frick GS, Madesh M, Ruiz-Stewart I, Schulz S, Hajnoczky G, Waldman SA. Proliferative signaling by store-operated calcium channels opposes colon cancer cell cytostasis induced by bacterial enterotoxins. J Pharmacol Exp Ther, 2005, 314: 1013–1022
Koslowski M, Sahin U, Dhaene K, Huber C, Tureci O. MS4A12 is a colon-selective store-operated calcium channel promoting malignant cell processes. Cancer Res, 2008, 68: 3458–3466
Vanden Abeele F, Roudbaraki M, Shuba Y, Skryma R, Prevarskaya N. Store-operated Ca2+ current in prostate cancer epithelial cells. Role of endogenous Ca2+ transporter type 1. J Biol Chem, 2003, 278: 15381–15389
Vanden Abeele F, Shuba Y, Roudbaraki M, Lemonnier L, Vanoverberghe K, Mariot P, Skryma R, Prevarskaya N. Store-operated Ca2+ channels in prostate cancer epithelial cells: function, regulation, and role in carcinogenesis. Cell Calcium, 2003, 33: 357–373
Skryma R, Mariot P, Bourhis XL, Coppenolle FV, Shuba Y, Vanden Abeele F, Legrand G, Humez S, Boilly B, Prevarskaya N. Store depletion and store-operated Ca2+ current in human prostate cancer lncap cells: involvement in apoptosis. J Physiol, 2000, 527 (Pt 1): 71–83
Pigozzi D, Ducret T, Tajeddine N, Gala JL, Tombal B, Gailly P. Calcium store contents control the expression of TRPC1, TRPC3 and TRPV6 proteins in lncap prostate cancer cell line. Cell Calcium, 2006, 39: 401–415
Pan Z, Bhat MB, Nieminen AL, Ma J. Synergistic movements of Ca(2+) and Bax in cells undergoing apoptosis. J Biol Chem, 2001, 276: 32257–32263
Lin PH, Pan Z, Zheng L, Li N, Danielpour D, Ma JJ. Overexpression of Bax sensitizes prostate cancer cells to TGF-beta induced apoptosis. Cell Res, 2005, 15: 160–166
Kokoska ER, Smith GS, Miller TA. Nonsteroidal anti-inflammatory drugs attenuate proliferation of colonic carcinoma cells by blocking epidermal growth factor-induced Ca++ mobilization. J Gastrointest Surg, 2000, 4: 150–161
Berna-Erro A, Woodard GE, Rosado JA. Orais and STIMs: physiological mechanisms and disease. J Cell Mol Med, 2012, 16: 407–424
Feske S. Immunodeficiency due to defects in store-operated calcium entry. Ann New York Acad Sci, 2011, 1238: 74–90
Fuchs S, Rensing-Ehl A, Speckmann C, Bengsch B, Schmitt-Graeff A, Bondzio I, Maul-Pavicic A, Bass T, Vraetz T, Strahm B, Ankermann T, Benson M, Caliebe A, Folster-Holst R, Kaiser P, Thimme R, Schamel WW, Schwarz K, Feske S, Ehl S. Antiviral and regulatory T cell immunity in a patient with stromal interaction molecule 1 deficiency. J Immunol, 2012, 188: 1523–1533
Le Deist F, Capiod T. Immunodeficiencies and pathologies associated with mutations in STIM/Orai, a membrane complex in the heart of calcium signalling. Med Sci, 2011, 27: 737–745
Shaw PJ, Feske S. Physiological and pathophysiological functions of SOCE in the immune system. Front Biosci (Elite Ed), 2012, 4: 2253–2268
Verbsky JW, Chatila TA. T-regulatory cells in primary immune deficiencies. Curr Opin Allergy Clin Immunol, 2011, 11: 539–544
Motiani RK, Hyzinski-Garcia MC, Zhang X, Henkel MM, Abdullaev IF, Kuo YH, Matrougui K, Mongin AA, Trebak M. STIM1 and Orai1 mediate CRAC channel activity and are essential for human glioblastoma invasion. Pflugers Arch, 2013, 465: 1249–1260
Kondratska K, Kondratskyi A, Yassine M, Lemonnier L, Lepage G, Morabito A, Skryma R, Prevarskaya N. Orai1 and STIM1 mediate SOCE and contribute to apoptotic resistance of pancreatic adenocarcinoma. Biochim Biophys Acta, 2014, 1843: 2263–2269
Flourakis M, Lehen’kyi V, Beck B, Raphael M, Vandenberghe M, Abeele FV, Roudbaraki M, Lepage G, Mauroy B, Romanin C, Shuba Y, Skryma R, Prevarskaya N. Orai1 contributes to the establishment of an apoptosis-resistant phenotype in prostate cancer cells. Cell Death Dis, 2010, 1: e75
Dubois C, Vanden Abeele F, Lehen’kyi V, Gkika D, Guarmit B, Lepage G, Slomianny C, Borowiec AS, Bidaux G, Benahmed M, Shuba Y, Prevarskaya N. Remodeling of channel-forming Orai proteins determines an oncogenic switch in prostate cancer. Cancer cell, 2014, 26: 19–32
Zhu H, Zhang H, Jin F, Fang M, Huang M, Yang CS, Chen T, Fu L, Pan Z. Elevated Orai1 expression mediates tumor-promoting intracellular Ca2+ oscillations in human esophageal squamous cell carcinoma. Oncotarget, 2014, 5: 3455–3471
Kim JH, Lkhagvadorj S, Lee MR, Hwang KH, Chung HC, Jung JH, Cha SK, Eom M. Orai1 and STIM1 are critical for cell migration and proliferation of clear cell renal cell carcinoma. Biochem Biophys Res Commun, 2014, 448: 76–82
Weidinger C, Shaw PJ, Feske S. STIM1 and STIM2-mediated Ca(2+) influx regulates antitumour immunity by CD8(+) T cells. EMBO Mol Med, 2013, 5: 1311–1321
Oh-Hora M, Yamashita M, Hogan PG, Sharma S, Lamperti E, Chung W, Prakriya M, Feske S, Rao A. Dual functions for the endoplasmic reticulum calcium sensors STIM1 and STIM2 in T cell activation and tolerance. Nat Immunol, 2008, 9: 432–443
Motiani RK, Zhang X, Harmon KE, Keller RS, Matrougui K, Bennett JA, Trebak M. Orai3 is an estrogen receptor α-regulated Ca2+ channel that promotes tumorigenesis. FASEB J, 2013, 27: 63–75
Ay AS, Benzerdjerb N, Sevestre H, Ahidouch A, Ouadid-Ahidouch H. Orai3 constitutes a native store-operated calcium entry that regulates non small cell lung adenocarcinoma cell proliferation. PLoS One, 2013, 8: e72889
Chantome A, Potier-Cartereau M, Clarysse L, Fromont G, Marionneau-Lambot S, Gueguinou M, Pages JC, Collin C, Oullier T, Girault A, Arbion F, Haelters JP, Jaffres PA, Pinault M, Besson P, Joulin V, Bougnoux P, Vandier C. Pivotal role of the lipid Raft SK3-Orai1 complex in human cancer cell migration and bone metastases. Cancer Res, 2013, 73: 4852–4861
Hou X, Pedi L, Diver MM, Long SB. Crystal structure of the calcium release-activated calcium channel Orai. Science, 2012, 338: 1308–1313
Li Z, Liu L, Deng Y, Ji W, Du W, Xu P, Chen L, Xu T. Graded activation of CRAC channel by binding of different numbers of STIM1 to Orai1 subunits. Cell Res, 2011, 21: 305–315
Hoover PJ, Lewis RS. Stoichiometric requirements for trapping and gating of Ca2+ release-activated Ca2+ (CRAC) channels by stromal interaction molecule 1 (STIM1). Proc Natl Acad Sci USA, 2011, 108: 13299–13304
Wang X, Wang Y, Zhou Y, Hendron E, Mancarella S, Andrake MD, Rothberg BS, Soboloff J, Gill DL. Distinct Orai-coupling domains in STIM1 and STIM2 define the Orai-activating site. Nat Commun, 2014, 5: 3183
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Pan, Z., Ma, J. Open Sesame: treasure in store-operated calcium entry pathway for cancer therapy. Sci. China Life Sci. 58, 48–53 (2015). https://doi.org/10.1007/s11427-014-4774-3
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DOI: https://doi.org/10.1007/s11427-014-4774-3