Store-Operated Calcium Entry in Cancer Stem Cells

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		Isaac Jardin	--	2700	2022-04-28 13:49:53	\|
2	update layout and references	Amina Yu	Meta information modification	2700	2022-04-29 05:16:21	\|

This entry is adapted from the peer-reviewed paper 10.3390/cells11081332

Store-Operated Calcium Entry (SOCE), a major mechanism for Ca2+influx from the extracellular medium into excitable and non-excitable cells, is physiologically triggered by the activation of phospholipase C (PLC) and the production of IP3, which subsequently leads to the release of Ca2+from intracellular stores, mainly the ER, resulting in the activation of store-operated calcium channels in the plasma membrane and a rapid increase in cytosolic Ca2+concentration. SOCE is an extremely complex biological mechanism, with high dependency on the pattern of expression of its components-STIMs, Orai, and TRPC proteins- and its modulators in each cell type. Since the last decades of the 20th century, several studies, both in vivo and in vitro, have reported that an altered expression pattern of the proteins that mediate SOCE leads to unbalanced Ca2+homeostasis, which might contribute to tumor development, poor prognosis, and chemotherapeutic drug resistance.

store-operated calcium entry Orai1 cancer stem cells

1. Introduction

Normal stem cells are undifferentiated or partially differentiated cells that are characterized by their ability to self-renew, the process of bringing about indefinitely more cells of the same type, as well as to differentiate in more specialized mature cells. The term “stem cell” was coined by Ernst Haeckel in 1868 to describe the ancestor unicellular organism from which all multicellular organisms were supposed to evolve ^[1]. Normal stem cells can be found from the early embryos to the mature subject, where they can be present in different tissues, including the bone marrow, skin and hair follicles, muscle, brain, and epithelia, among others ^[2].

Cancer stem cells (CSC), also known as tumor-initiating cells, share features of both cancer and stem cells. These cells constitute a sub-population of tumor-resident malignant cells responsible for recurrence, metastasis formation, and chemoresistance. Experimental evidence indicates that CSC exhibit “stemness” properties, that is, the ability of cells to perpetuate their lineage, to bring about differentiated cells and to interact with their microenvironment to maintain a balance between quiescence, proliferation, and regeneration ^[3]. According to this, CSC exhibit low proliferative rates, self-renewing capacity, propensity to differentiate into proliferating tumor cells, resistance to apoptosis and senescence, as well as to chemo- and radio-therapy, evasion of immune attack, and are responsible for invasion and metastases ^[4]^[5].

2. Store-Operated Calcium Entry in Cancer Stem Cells and Cancer Hallmarks

Store-Operated Calcium Entry (SOCE), a major mechanism for Ca²⁺ influx from the extracellular medium into excitable and non-excitable cells, is physiologically triggered by the activation of phospholipase C (PLC) and the production of IP₃, which subsequently leads to the release of Ca²⁺ from intracellular stores, mainly the ER, resulting in the activation of store-operated calcium channels in the plasma membrane and a rapid increase in cytosolic Ca²⁺ concentration ^[6]^[7]. SOCE is an extremely complex biological mechanism, with high dependency on the pattern of expression of its components-STIMs, Orai, and TRPC proteins- and its modulators in each cell type. Since the last decades of the 20th century, several studies, both in vivo and in vitro, have reported that an altered expression pattern of the proteins that mediate SOCE leads to unbalanced Ca²⁺ homeostasis, which might contribute to tumor development, poor prognosis, and chemotherapeutic drug resistance ^[8].

The proteins of the STromal Interaction Molecule (STIM) family, STIM1 and STIM2, and their splice variants, possess a single transmembrane domain, with the N-region located either in the ER lumen or the extracellular medium, and a long cytosolic C-region ^[9]^[10]. Both, N- and C-terminal regions, present several key domains that enact STIM proteins’ double function upon a diminishment of the luminal Ca²⁺ concentration in the intracellular stores: (1) as the Ca²⁺ sensors of intracellular organelles, mediated by EF-hand Ca²⁺-binding domains in the N-terminus; and (2) as the transmitters of the filling state of intracellular Ca²⁺ stores to, and the activators of, Ca²⁺ channels in the plasma membrane. The latter is achieved by direct interaction between different domains within the STIM cytosolic C-region and the store-operated Ca²⁺ channels (STIM proteins structure is reviewed in ^[11]^[12]^[13]).

SOCE could be mediated by two types of channels with different biophysical properties: (1) the Ca²⁺ Release-Activated Ca²⁺ (CRAC) channels that exhibit high Ca²⁺ selectivity and an inwardly rectifying current, termed I_CRAC, which its exclusively conducted by members of the Orai family ^[14]; and (2) the Store-Operated Ca²⁺ (SOC) channels, responsible to mediate a non-selective cation current denominated I_SOC, formed by both, Orai1 and TRPC1, the first identified member of the canonical Transient Receptor Potential (TRPC) channel subfamily ^[15]^[16].

Orai1 was initially characterized as the main component of CRAC channel during a RNAi screening in 2006, when it was found that the Orai1 R91W mutation was responsible for abrogated CRAC channel function, critical for T-cell activation, in immunodeficient patients ^[17]. Orai1 and its paralogues, Orai2 and Orai3, present a unique structure among other Ca²⁺ channels, with four transmembrane domains spanning the PM and both, N- and C-terminus, facing the cytoplasm ^[18]. Originally, it was thought that Orai channels were formed by a homo-tetramer ^[19]; however, the crystal structure from Drosophila melanogaster Orai1 (dOrai1) presented a hexamer configuration, with the ion pore formed by the first transmembrane domain of the Orai subunits and located in the center of the complex surrounded by the remaining Orai plasma membrane domains ^[20]. The three members of the Orai family are capable to mediate store dependent Ca²⁺ influx, each of them with different biophysical properties that are extensively discussed here ^[21]^[22]. Some years ago, a shorter splicing variant for Orai1, Orai1β, lacking 64 aa in the N-terminus but able to generate functional Orai1 channels, was identified. Orai1β can be fully activated by STIM1 in a store-dependent manner but exhibits differential inactivation patterns as compared with the long variant, Orai1α ^[16]. In addition, recent studies have shown that Orai proteins might have a role in non-capacitative Ca²⁺ influx forming heteromers, such as the arachidonate-regulated Ca²⁺ channels (ARC), where three Orai1 and two Orai3 subunits form a pentamer ^[23], or interacting with other proteins to mediate store-independent Ca²⁺ influx ^[24].

TRPC1 belongs to the TRP channel superfamily, whose members ubiquitously mediate ion fluxes across the whole animal kingdom in a cell type-dependent manner ^[25]. All TRPs possess a similar structure with six transmembrane domains and the pore located between the 5th and 6th transmembrane regions. TRPs exhibit N- and C-terminus of variable length, containing the TRP box and different functional domains, subfamily-dependent, which participate in the functions of TRP channels and their relationship with other molecules and proteins. A functional TRP channel is composed by four TRP subunits forming either a homo- or hetero-tetramer ^[26]^[27]. Prior to Orai1 characterization, TRPC1 was a suggested candidate as the channel responsible for SOCE as STIM1 is able to interact and activate TRPC1 channels ^[28]^[29]. The current hypothesis suggests that TRPC1, together with Orai1, is involved in the generation of I_SOC currents ^[16]^[30]^[31]^[32]. TRPC1 channels, permeable to Na⁺, Ca²⁺, and Cs⁺ ^[33], are less selective for Ca²⁺ than Orai1 and allow a massive ion influx from the extracellular medium, required for the maintenance of SOCE and store replenishment ^[34].

Several stimuli might trigger intracellular Ca²⁺ stores depletion that will be sensed by STIM proteins. Minor reductions in luminal Ca²⁺ concentration will be detected by STIM2, which in turn, would momentarily trigger the opening of CRAC channels, allowing Ca²⁺ influx from the extracellular medium that will quickly be reintroduced into the stores by Ca²⁺-ATPase pumps to revert to resting conditions ^[11]. More extensive discharge of intracellular Ca²⁺ stores would trigger the activation of STIM1, in addition to STIM2, which will fully generate the opening of CRAC channels, subsequently followed by a rapid and transient Ca²⁺ entry ^[14]^[35]^[36]^[37]. Ca²⁺ entry conducted by Orai1 will be severely inhibited after few milliseconds by Ca²⁺ itself ^[38]^[39] as well as after a longer period of time by the interaction of Orai1 N- and C-terminus with different proteins, such as SARAF ^[40]^[41]^[42] or by Orai1 serine phosphorylation at the N-terminus by kinases such as PKC or PKA ^[43]^[44]. Ca²⁺ influx through Orai1 leads to the recruitment of TRPC1 at the plasma membrane, which conducts further Ca²⁺ influx to reach the critical cytosolic Ca²⁺ concentration required for the physiological response evoked by the stimulus ^[34]^[45]. Next, the excess of intracellular Ca²⁺ is speedily removed, either by reintroducing the ion into the ER or by its extrusion to the extracellular medium via Ca²⁺-ATPases ^[46]^[47]. When agonist stimulation ceases, replenishment of the Ca²⁺ stores leads to the incorporation of Ca²⁺ to STIM1/2 EF-hand domains, which return these proteins to their quiescent conformation, leading to the deactivation of SOCE ^[10]^[35].

The number of studies linking SOCE proteins with cancer stem cell properties is growing at an amazingly fast pace; however, the knowledge is still extremely limited. Regarding STIM proteins, it is known that STIM1 associates with the hypoxia-inducible factor-1 alpha (HIF-1α) modulating each other, in a reciprocal dependency, in hypoxic hepatocarcinoma cells (HCCs). HIF-1α up-regulates STIM1 transcription, which in turn, induces higher SOCE, activating the CaMKII and P300 pathways, which are required for the accumulation of HIF-1α in HCCs ^[48].

Even less is known about the role of TRPC1 in CSC, since some of the inhibitors used to block SOCE, act over both Orai1 and TRPC1 channels. For instance, treatment with SKF96365, a SOCE inhibitor, impairs CSC proliferation in the glioblastoma stem-like cell line, TG1, triggering these cells to adopt a quiescent state by up-regulation of CDKN1A and G0S2 and the down-regulation of CCNB1 genes ^[49]. Similarly, SOCE impairment by SKF96365 in liver cancer stem cells (LCSCs) resulted in a drastic reduction in their ability to form spheroids, suppressing at the same time the expression of stemness-related genes. SOCE is activated in LCSC via the fibroblast growth factor 19 (FGF19), promoting the nuclear translocation of NFATc2 and self-renewal ^[50]. Even when the expression of Orai and STIM proteins was checked in both studies, TRPC1 was not considered and might be a possible candidate for future approaches.

3. Functional Role of Orai in Cancer Stem Cells and Cancer Hallmarks

As described above, native CRAC channels are hexameric structures comprised by the heteromeric association of Orai1, Orai2, and Orai3. Although all Orai family members can conform the channel, Orai2 and Orai3 also act as Ca²⁺ current modulators due to their lower Ca²⁺ conductivity and greater fast Ca²⁺-dependent inactivation as compared to Orai1 ^[39]^[51]. Several studies have demonstrated that the three Orai proteins are overexpressed in tumor samples and different human cancer cell lines compared with their non-tumorigenic counterpart cell lines. Hence, Orai1 is overexpressed in oral/oropharyngeal squamous cell carcinoma cells (OSCC) ^[52]^[53], liver ^[54], and breast cancer cells ^[55]^[56], Orai2 expression is increased in gastric ^[57], breast ^[58], oral ^[53], and acute myeloid leukemia cancer cells ^[59], while Orai3 expression is enhanced in the luminal breast cancer subtype ^[56]^[60], as well as in lung ^[61], pancreatic ^[62], and prostate cancer cells ^[63] (for a more extensive one see ^[64]^[65]^[66]^[67]^[68]). Using pharmacological or gene silencing approaches, to inhibit protein function or to avoid protein expression, respectively, the mentioned studies showed that Orai proteins play a crucial role in both tumorigenesis and the development and maintenance of different cancer hallmarks, including resistance to apoptosis, proliferation, migration, invasion, and metastasis via SOCE. However, as mentioned above, Orai1 can also mediate cancer progression by regulating and driving different Ca²⁺ influx pathways that are independent of the filling state of intracellular Ca²⁺ stores ^[24]. These pathways include: (1) the arachidonic acid-regulated Ca²⁺ current mediated by a Orai1/3 channel ^[63]^[69]^[70], (2) the constitutive Ca²⁺ influx mediated by the physical interaction between Orai1 and secretory pathway Ca²⁺-ATPase-2 ^[71]^[72]^[73], and (3) the Ca²⁺ influx mediated by the physical and functional interaction of Orai1 with the small conductance Ca²⁺-activated K⁺ channel 3 ^[74]^[75] or with the voltage-dependent Kv10.1 channel in the plasma membrane ^[76]^[77]. In the latter, a reciprocal positive feedback loop promotes the activation of both K⁺ channels by Orai1-mediated Ca²⁺ entry, which in turn leads to plasma membrane hyperpolarization, thus maintaining the driving force for Ca²⁺ influx and Ca²⁺ entry through Orai1 channels ^[74]^[78]^[79].

The role of Orai family proteins has also been described in the induction of CSC phenotype in a variety of cancers, such as glioblastoma, lung, and OSCC cancer cells. This CSC phenotype includes self-renewal capacity, tumor spheres formation, drug resistance, increased migration ability, and enhanced expression of stemness-related transcription factors and CSC-related markers ^[52]^[80]^[81]. Lee et al. demonstrated that Orai1, the predominant Orai family member in OSCC, is overexpressed in OSCC-derived CSC and its function is required for the maintenance of stemness and CSC phenotype through NFAT signaling pathway. Hence, Orai1 mediates the enhanced expression of stemness-related transcription factors, such as Nanog, Oct4 or Sox2, and promotes some CSC-related markers, including an increased ALDH1 activity and a higher CSC-related gene expression (Ezh2, Gli1, Hes1, Zeb2, FGF4, and IL4). The inhibition of Orai1 function in human tongue squamous carcinoma cell lines SCC4 and HOK-16B BapT by a pharmacological approach, using the Orai1 specific small molecular blocker compound 5D, impaired self-renewal capacity and reduced migration and invasion abilities in these cancer cells. Comparable results were also obtained by two different genetic approaches, using a specific siRNA to reduce Orai1 gene expression and inducing the overexpression of an Orai1 dominant negative mutant. Furthermore, Orai1 overexpression using viral vectors promoted CSC phenotype in non-tumorigenic immortalized oral epithelial cells HOK-16B ^[52]. Using related approaches, Singh et al. demonstrated that Orai1 and Orai2 overexpression is required for cell proliferation, migration, and colonization in SAS human tongue carcinoma cell line, processes that were found to be dependent on Akt/mTOR/NF-κB signaling pathway activation ^[53]. Analogous results were reported in glioblastoma stem cells derived from different human glioblastoma surgical samples. In these cells, the treatment with YM-58483, a CRAC current inhibitor, or with GSK-7975A, a more specific inhibitor of Orai1-mediated Ca²⁺ current, promoted a decrease in Sox2 expression, effect that was associated with reduced spheres formation and with the inhibition of their proliferation and self-renewal capacities ^[81]. Orai1 has been also related with chemoresistance, event that has been widely associated with CSC phenotype in cancer cells as previously mentioned. Hence, it has been demonstrated that ectopic overexpression of Orai1, using a plasmid vector, inhibited 5-fluorouracil-induced cell death in HepG2 hepatocarcinoma cells; meanwhile, Orai1 gene expression knockdown promoted the autophagic cell death induced by this pharmacological compound ^[54]. Similar findings were observed in cisplatin-resistant A2780 ovary carcinoma cells, in which Orai1 expression and SOCE are increased compared to therapy-sensitive parental cells. Pharmacological inhibition of Orai1 in cisplatin-resistant A2780 cells, using 2-aminoethoxydiphenyl borate (2-APB), promoted cisplatin-induced apoptotic cell death similarly to those observed in therapy-sensitive A2780 cells ^[82]. Conversely, an opposite effect has been reported in prostate cancer cells since the downregulation of Orai1 expression, caused by steroid-deprived conditions or by using specific siRNA against Orai1, and the impairment of Orai1 function by the overexpression of two Orai1 mutants, Orai1 R91W and Orai1 L273S, prevented the apoptotic cell death induced by different pharmacological compounds, including thapsigargin, TNFα, cisplatin, and oxaliplatin. Furthermore, the restoration of Orai1 expression in steroid-deprived cells by transfection with a Orai1 plasmid vector promoted the loss of chemoresistance in these cells ^[83].

Regarding the role of Orai3 in the CSC phenotype acquisition in cancer cells, it has been demonstrated that Orai3 overexpression is correlated with tumoral aggressiveness and chemoresistance acquisition in breast cancer cells ^[60]^[80]. Orai3 stable overexpressing T47D and MCF7 clones exhibited resistance to apoptotic cell death induced by thapsigargin, cisplatin, 5-fluorouracil, and paclitaxel compared with their parental cells transfected with the empty vector. This Orai3-dependent chemoresistance is acquired by ubiquitin ligase Nedd4-2-mediated p53 ubiquitination via the PI3K/Sgk-1 signaling pathway ^[60]. Previously, the same group demonstrated that Orai3 expression is also positively correlated with the oncogene c-myc expression in the ER-positive (luminal-like) breast cancer cell line MCF7 ^[84]. Daya et al. revealed that chemotherapy treatment increased Orai3 expression in primary human lung adenocarcinoma cells derived from bronchial biopsy specimens. Similar findings were reported in lung adenocarcinoma cell lines A549 and NCI-H23 after treatment with cisplatin. Interestingly, cisplatin treatment increased SOCE without affecting the expression of other proteins involved in CRAC current activation, such as STIM1, STIM2, and Orai1, even a slight decrease in the expression of Orai1 was observed in A549 cells. Orai3 gene expression knockdown using a specific siRNA enhanced cisplatin-induced apoptotic cell death in both lung adenocarcinoma cell lines, while Orai3 overexpression drastically reduced cisplatin-induced cell death and enhanced stemness in non-small cell lung cancer cells, as demonstrated by the enhanced expression of the stemness-related transcription factors Nanog and Sox2 via PI3K/AKT pathway, which resulted to be dependent on the increase in Orai3 expression ^[80].

References

Ramalho-Santos, M.; Willenbring, H. On the origin of the term “stem cell”. Cell Stem Cell 2007, 1, 35–38.
Soldner, F.; Jaenisch, R. Stem Cells, Genome Editing, and the Path to Translational Medicine. Cell 2018, 175, 615–632.
Aponte, P.M.; Caicedo, A. Stemness in Cancer: Stem Cells, Cancer Stem Cells, and Their Microenvironment. Stem Cells Int. 2017, 2017, 5619472.
Neuzil, J.; Stantic, M.; Zobalova, R.; Chladova, J.; Wang, X.; Prochazka, L.; Dong, L.; Andera, L.; Ralph, S.J. Tumour-initiating cells vs. ‘cancer stem’ cells and CD133: What’s in the name? Biochem. Biophys. Res. Commun. 2007, 355, 855–859.
Kabakov, A.; Yakimova, A.; Matchuk, O. Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy. Cells 2020, 9, 892.
Putney, J.W.; Bird, G.S. Cytoplasmic calcium oscillations and store-operated calcium influx. J. Physiol. 2008, 586, 3055–3059.
Putney, J.W., Jr. A model for receptor-regulated calcium entry. Cell Calcium 1986, 7, 1–12.
Jardin, I.; Rosado, J.A. STIM and calcium channel complexes in cancer. Biochim. Biophys. Acta 2016, 1863, 1418–1426.
Roos, J.; DiGregorio, P.J.; Yeromin, A.V.; Ohlsen, K.; Lioudyno, M.; Zhang, S.; Safrina, O.; Kozak, J.A.; Wagner, S.L.; Cahalan, M.D.; et al. STIM1, an essential and conserved component of store-operated Ca2+ channel function. J. Cell Biol. 2005, 169, 435–445.
Zhang, S.L.; Yu, Y.; Roos, J.; Kozak, J.A.; Deerinck, T.J.; Ellisman, M.H.; Stauderman, K.A.; Cahalan, M.D. STIM1 is a Ca2+ sensor that activates CRAC channels and migrates from the Ca2+ store to the plasma membrane. Nature 2005, 437, 902–905.
Berna-Erro, A.; Jardin, I.; Salido, G.M.; Rosado, J.A. Role of STIM2 in cell function and physiopathology. J. Physiol. 2017, 595, 3111–3128.
Grabmayr, H.; Romanin, C.; Fahrner, M. STIM Proteins: An Ever-Expanding Family. Int. J. Mol. Sci. 2020, 22, 378.
Fahrner, M.; Romanin, C. The many states of STIM1. Elife 2021, 10, e75174.
Yuan, J.P.; Zeng, W.; Dorwart, M.R.; Choi, Y.J.; Worley, P.F.; Muallem, S. SOAR and the polybasic STIM1 domains gate and regulate Orai channels. Nat. Cell Biol. 2009, 11, 337–343.
Zhang, Z.Y.; Pan, L.J.; Zhang, Z.M. Functional interactions among STIM1, Orai1 and TRPC1 on the activation of SOCs in HL-7702 cells. Amino Acids 2009, 39, 195–204.
Desai, P.N.; Zhang, X.; Wu, S.; Janoshazi, A.; Bolimuntha, S.; Putney, J.W.; Trebak, M. Multiple types of calcium channels arising from alternative translation initiation of the Orai1 message. Sci. Signal. 2015, 8, ra74.
Feske, S.; Gwack, Y.; Prakriya, M.; Srikanth, S.; Puppel, S.H.; Tanasa, B.; Hogan, P.G.; Lewis, R.S.; Daly, M.; Rao, A. A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function. Nature 2006, 441, 179–185.
Zhou, Y.; Ramachandran, S.; Oh-Hora, M.; Rao, A.; Hogan, P.G. Pore architecture of the ORAI1 store-operated calcium channel. Proc. Natl. Acad. Sci. USA 2010, 107, 4896–4901.
Mignen, O.; Thompson, J.L.; Shuttleworth, T.J. Orai1 subunit stoichiometry of the mammalian CRAC channel pore. J. Physiol. 2008, 586, 419–425.
Hou, X.; Pedi, L.; Diver, M.M.; Long, S.B. Crystal structure of the calcium release-activated calcium channel Orai. Science 2012, 338, 1308–1313.
Butorac, C.; Krizova, A.; Derler, I. Review: Structure and Activation Mechanisms of CRAC Channels. Adv. Exp. Med. Biol. 2020, 1131, 547–604.
Qiu, R.; Lewis, R.S. Structural features of STIM and Orai underlying store-operated calcium entry. Curr. Opin. Cell Biol. 2019, 57, 90–98.
Shuttleworth, T.J. Arachidonic acid, ARC channels, and Orai proteins. Cell Calcium 2009, 45, 602–610.
Cantonero, C.; Sanchez-Collado, J.; Gonzalez-Nunez, M.A.; Salido, G.M.; Lopez, J.J.; Jardin, I.; Rosado, J.A. Store-independent Orai1-mediated Ca2+ entry and cancer. Cell Calcium 2019, 80, 1–7.
Clapham, D.E. TRP channels as cellular sensors. Nature 2003, 426, 517–524.
Guo, W.; Chen, L. Recent progress in structural studies on canonical TRP ion channels. Cell Calcium 2019, 83, 102075.
Lopez, J.J.; Jardin, I.; Albarran, L.; Sanchez-Collado, J.; Cantonero, C.; Salido, G.M.; Smani, T.; Rosado, J.A. Molecular Basis and Regulation of Store-Operated Calcium Entry. Adv. Exp. Med. Biol. 2020, 1131, 445–469.
Huang, G.N.; Zeng, W.; Kim, J.Y.; Yuan, J.P.; Han, L.; Muallem, S.; Worley, P.F. STIM1 carboxyl-terminus activates native SOC, I(crac) and TRPC1 channels. Nat. Cell Biol. 2006, 8, 1003–1010.
Yuan, J.P.; Zeng, W.; Huang, G.N.; Worley, P.F.; Muallem, S. STIM1 heteromultimerizes TRPC channels to determine their function as store-operated channels. Nat. Cell Biol. 2007, 9, 636–645.
Cheng, K.T.; Liu, X.; Ong, H.L.; Ambudkar, I.S. Functional requirement for Orai1 in store-operated TRPC1-STIM1 channels. J. Biol. Chem. 2008, 283, 12935–12940.
Lee, K.P.; Choi, S.; Hong, J.H.; Ahuja, M.; Graham, S.; Ma, R.; So, I.; Shin, D.M.; Muallem, S.; Yuan, J.P. Molecular determinants mediating gating of Transient Receptor Potential Canonical (TRPC) channels by stromal interaction molecule 1 (STIM1). J. Biol. Chem. 2014, 289, 6372–6382.
Jardin, I.; Lopez, J.J.; Salido, G.M.; Rosado, J.A. Orai1 mediates the interaction between STIM1 and hTRPC1 and regulates the mode of activation of hTRPC1-forming Ca2+ channels. J. Biol. Chem. 2008, 283, 25296–25304.
Zitt, C.; Zobel, A.; Obukhov, A.G.; Harteneck, C.; Kalkbrenner, F.; Luckhoff, A.; Schultz, G. Cloning and functional expression of a human Ca2+-permeable cation channel activated by calcium store depletion. Neuron 1996, 16, 1189–1196.
Cheng, K.T.; Liu, X.; Ong, H.L.; Swaim, W.; Ambudkar, I.S. Local Ca2+ entry via Orai1 regulates plasma membrane recruitment of TRPC1 and controls cytosolic Ca2+ signals required for specific cell functions. PLoS Biol. 2011, 9, e1001025.
Stathopulos, P.B.; Zheng, L.; Li, G.Y.; Plevin, M.J.; Ikura, M. Structural and mechanistic insights into STIM1-mediated initiation of store-operated calcium entry. Cell 2008, 135, 110–122.
Muik, M.; Frischauf, I.; Derler, I.; Fahrner, M.; Bergsmann, J.; Eder, P.; Schindl, R.; Hesch, C.; Polzinger, B.; Fritsch, R.; et al. Dynamic coupling of the putative coiled-coil domain of ORAI1 with STIM1 mediates ORAI1 channel activation. J. Biol. Chem. 2008, 283, 8014–8022.
Park, C.Y.; Hoover, P.J.; Mullins, F.M.; Bachhawat, P.; Covington, E.D.; Raunser, S.; Walz, T.; Garcia, K.C.; Dolmetsch, R.E.; Lewis, R.S. STIM1 clusters and activates CRAC channels via direct binding of a cytosolic domain to Orai1. Cell 2009, 136, 876–890.
Derler, I.; Fahrner, M.; Muik, M.; Lackner, B.; Schindl, R.; Groschner, K.; Romanin, C. A CRAC modulatory domain (CMD) within STIM1 mediates fast Ca2+-dependent inactivation of ORAI1 channels. J. Biol. Chem. 2009, 284, 24933–24938.
Lee, K.P.; Yuan, J.P.; Zeng, W.; So, I.; Worley, P.F.; Muallem, S. Molecular determinants of fast Ca2+-dependent inactivation and gating of the Orai channels. Proc. Natl. Acad. Sci. USA 2009, 106, 14687–14692.
Albarran, L.; Lopez, J.J.; Jardin, I.; Sanchez-Collado, J.; Berna-Erro, A.; Smani, T.; Camello, P.J.; Salido, G.M.; Rosado, J.A. EFHB is a Novel Cytosolic Ca2+ Sensor That Modulates STIM1-SARAF Interaction. Cell Physiol. Biochem. 2018, 51, 1164–1178.
Jha, A.; Ahuja, M.; Maleth, J.; Moreno, C.M.; Yuan, J.P.; Kim, M.S.; Muallem, S. The STIM1 CTID domain determines access of SARAF to SOAR to regulate Orai1 channel function. J. Cell Biol. 2013, 202, 71–79.
Palty, R.; Raveh, A.; Kaminsky, I.; Meller, R.; Reuveny, E. SARAF inactivates the store operated calcium entry machinery to prevent excess calcium refilling. Cell 2012, 149, 425–438.
Kawasaki, T.; Ueyama, T.; Lange, I.; Feske, S.; Saito, N. Protein kinase C-induced phosphorylation of Orai1 regulates the intracellular Ca2+ level via the store-operated Ca2+ channel. J. Biol. Chem. 2010, 285, 25720–25730.
Zhang, X.; Pathak, T.; Yoast, R.; Emrich, S.; Xin, P.; Nwokonko, R.M.; Johnson, M.; Wu, S.; Delierneux, C.; Gueguinou, M.; et al. A calcium/cAMP signaling loop at the ORAI1 mouth drives channel inactivation to shape NFAT induction. Nat. Commun. 2019, 10, 1971.
Sanchez-Collado, J.; Lopez, J.J.; Jardin, I.; Berna-Erro, A.; Camello, P.J.; Cantonero, C.; Smani, T.; Salido, G.M.; Rosado, J.A. Orai1alpha, but not Orai1beta, co-localizes with TRPC1 and is required for its plasma membrane location and activation in HeLa cells. Cell Mol. Life Sci. 2022, 79, 33.
Redondo, P.C.; Rosado, J.A.; Pariente, J.A.; Salido, G.M. Collaborative effect of SERCA and PMCA in cytosolic calcium homeostasis in human platelets. J. Physiol. Biochem. 2005, 61, 507–516.
Elaib, Z.; Saller, F.; Bobe, R. The Calcium Entry-Calcium Refilling Coupling. Adv. Exp. Med. Biol. 2016, 898, 333–352.
Li, Y.; Guo, B.; Xie, Q.; Ye, D.; Zhang, D.; Zhu, Y.; Chen, H.; Zhu, B. STIM1 Mediates Hypoxia-Driven Hepatocarcinogenesis via Interaction with HIF-1. Cell Rep. 2015, 12, 388–395.
Aulestia, F.J.; Neant, I.; Dong, J.; Haiech, J.; Kilhoffer, M.C.; Moreau, M.; Leclerc, C. Quiescence status of glioblastoma stem-like cells involves remodelling of Ca2+ signalling and mitochondrial shape. Sci. Rep. 2018, 8, 9731.
Wang, J.; Zhao, H.; Zheng, L.; Zhou, Y.; Wu, L.; Xu, Y.; Zhang, X.; Yan, G.; Sheng, H.; Xin, R.; et al. FGF19/SOCE/NFATc2 signaling circuit facilitates the self-renewal of liver cancer stem cells. Theranostics 2021, 11, 5045–5060.
Yoast, R.E.; Emrich, S.M.; Zhang, X.; Xin, P.; Johnson, M.T.; Fike, A.J.; Walter, V.; Hempel, N.; Yule, D.I.; Sneyd, J.; et al. The native ORAI channel trio underlies the diversity of Ca2+ signaling events. Nat. Commun. 2020, 11, 2444.
Lee, S.H.; Rigas, N.K.; Lee, C.R.; Bang, A.; Srikanth, S.; Gwack, Y.; Kang, M.K.; Kim, R.H.; Park, N.H.; Shin, K.H. Orai1 promotes tumor progression by enhancing cancer stemness via NFAT signaling in oral/oropharyngeal squamous cell carcinoma. Oncotarget 2016, 7, 43239–43255.
Singh, A.K.; Roy, N.K.; Bordoloi, D.; Padmavathi, G.; Banik, K.; Khwairakpam, A.D.; Kunnumakkara, A.B.; Sukumar, P. Orai-1 and Orai-2 regulate oral cancer cell migration and colonisation by suppressing Akt/mTOR/NF-kappaB signalling. Life Sci. 2020, 261, 118372.
Tang, B.D.; Xia, X.; Lv, X.F.; Yu, B.X.; Yuan, J.N.; Mai, X.Y.; Shang, J.Y.; Zhou, J.G.; Liang, S.J.; Pang, R.P. Inhibition of Orai1-mediated Ca2+ entry enhances chemosensitivity of HepG2 hepatocarcinoma cells to 5-fluorouracil. J. Cell. Mol. Med. 2017, 21, 904–915.
Jardin, I.; Diez-Bello, R.; Lopez, J.J.; Redondo, P.C.; Salido, G.M.; Smani, T.; Rosado, J.A. TRPC6 Channels Are Required for Proliferation, Migration and Invasion of Breast Cancer Cell Lines by Modulation of Orai1 and Orai3 Surface Exposure. Cancers 2018, 10, 331.
Motiani, R.K.; Abdullaev, I.F.; Trebak, M. A novel native store-operated calcium channel encoded by Orai3: Selective requirement of Orai3 versus Orai1 in estrogen receptor-positive versus estrogen receptor-negative breast cancer cells. J. Biol. Chem. 2010, 285, 19173–19183.
Wu, S.; Chen, M.; Huang, J.; Zhang, F.; Lv, Z.; Jia, Y.; Cui, Y.Z.; Sun, L.Z.; Wang, Y.; Tang, Y.; et al. ORAI2 Promotes Gastric Cancer Tumorigenicity and Metastasis through PI3K/Akt Signaling and MAPK-Dependent Focal Adhesion Disassembly. Cancer Res. 2021, 81, 986–1000.
Sanchez-Collado, J.; Lopez, J.J.; Cantonero, C.; Jardin, I.; Regodon, S.; Redondo, P.C.; Gordillo, J.; Smani, T.; Salido, G.M.; Rosado, J.A. Orai2 Modulates Store-Operated Ca(2+) Entry and Cell Cycle Progression in Breast Cancer Cells. Cancers 2021, 14, 114.
Diez-Bello, R.; Jardin, I.; Salido, G.M.; Rosado, J.A. Orai1 and Orai2 mediate store-operated calcium entry that regulates HL60 cell migration and FAK phosphorylation. Biochim. Biophys. Acta Mol. Cell Res. 2017, 1864, 1064–1070.
Hasna, J.; Hague, F.; Rodat-Despoix, L.; Geerts, D.; Leroy, C.; Tulasne, D.; Ouadid-Ahidouch, H.; Kischel, P. Orai3 calcium channel and resistance to chemotherapy in breast cancer cells: The p53 connection. Cell Death Differ. 2018, 25, 693–707.
Benzerdjeb, N.; Sevestre, H.; Ahidouch, A.; Ouadid-Ahidouch, H. Orai3 is a predictive marker of metastasis and survival in resectable lung adenocarcinoma. Oncotarget 2016, 7, 81588–81597.
Arora, S.; Tanwar, J.; Sharma, N.; Saurav, S.; Motiani, R.K. Orai3 Regulates Pancreatic Cancer Metastasis by Encoding a Functional Store Operated Calcium Entry Channel. Cancers 2021, 13, 5937.
Dubois, C.; Vanden Abeele, F.; Lehen’kyi, V.; Gkika, D.; Guarmit, B.; Lepage, G.; Slomianny, C.; Borowiec, A.S.; Bidaux, G.; Benahmed, M.; et al. Remodeling of channel-forming ORAI proteins determines an oncogenic switch in prostate cancer. Cancer Cell 2014, 26, 19–32.
Tanwar, J.; Arora, S.; Motiani, R.K. Orai3: Oncochannel with therapeutic potential. Cell Calcium 2020, 90, 102247.
Chalmers, S.B.; Monteith, G.R. ORAI channels and cancer. Cell Calcium 2018, 74, 160–167.
Jardin, I.; Lopez, J.J.; Salido, G.M.; Rosado, J.A. Store-Operated Ca2+ Entry in Breast Cancer Cells: Remodeling and Functional Role. Int. J. Mol. Sci. 2018, 19, 4053.
Sanchez-Collado, J.; Jardin, I.; Lopez, J.J.; Ronco, V.; Salido, G.M.; Dubois, C.; Prevarskaya, N.; Rosado, J.A. Role of Orai3 in the Pathophysiology of Cancer. Int. J. Mol. Sci. 2021, 22, 11426.
Vashisht, A.; Trebak, M.; Motiani, R.K. STIM and Orai proteins as novel targets for cancer therapy. A Review in the Theme: Cell and Molecular Processes in Cancer Metastasis. Am. J. Physiol. Cell Physiol. 2015, 309, C457–C469.
Goswamee, P.; Pounardjian, T.; Giovannucci, D.R. Arachidonic acid-induced Ca2+ entry and migration in a neuroendocrine cancer cell line. Cancer Cell Int. 2018, 18, 30.
Fiorio Pla, A.; Grange, C.; Antoniotti, S.; Tomatis, C.; Merlino, A.; Bussolati, B.; Munaron, L. Arachidonic acid-induced Ca2+ entry is involved in early steps of tumor angiogenesis. Mol. Cancer Res. 2008, 6, 535–545.
Baron, S.; Vangheluwe, P.; Sepulveda, M.R.; Wuytack, F.; Raeymaekers, L.; Vanoevelen, J. The secretory pathway Ca2+-ATPase 1 is associated with cholesterol-rich microdomains of human colon adenocarcinoma cells. Biochim. Biophys. Acta 2010, 1798, 1512–1521.
Feng, M.; Grice, D.M.; Faddy, H.M.; Nguyen, N.; Leitch, S.; Wang, Y.; Muend, S.; Kenny, P.A.; Sukumar, S.; Roberts-Thomson, S.J.; et al. Store-independent activation of Orai1 by SPCA2 in mammary tumors. Cell 2010, 143, 84–98.
Feng, M.Y.; Rao, R. New insights into store-independent Ca2+ entry: Secretory pathway calcium ATPase 2 in normal physiology and cancer. Int. J. Oral. Sci. 2013, 5, 71–74.
Chantome, A.; Potier-Cartereau, M.; Clarysse, L.; Fromont, G.; Marionneau-Lambot, S.; Gueguinou, M.; Pages, J.C.; Collin, C.; Oullier, T.; Girault, A.; et al. Pivotal role of the lipid Raft SK3-Orai1 complex in human cancer cell migration and bone metastases. Cancer Res. 2013, 73, 4852–4861.
Gueguinou, M.; Harnois, T.; Crottes, D.; Uguen, A.; Deliot, N.; Gambade, A.; Chantome, A.; Haelters, J.P.; Jaffres, P.A.; Jourdan, M.L.; et al. SK3/TRPC1/Orai1 complex regulates SOCE-dependent colon cancer cell migration: A novel opportunity to modulate anti-EGFR mAb action by the alkyl-lipid Ohmline. Oncotarget 2016, 7, 36168–36184.
Badaoui, M.; Mimsy-Julienne, C.; Saby, C.; Van Gulick, L.; Peretti, M.; Jeannesson, P.; Morjani, H.; Ouadid-Ahidouch, H. Collagen type 1 promotes survival of human breast cancer cells by overexpressing Kv10.1 potassium and Orai1 calcium channels through DDR1-dependent pathway. Oncotarget 2018, 9, 24653–24671.
Hammadi, M.; Chopin, V.; Matifat, F.; Dhennin-Duthille, I.; Chasseraud, M.; Sevestre, H.; Ouadid-Ahidouch, H. Human ether a-gogo K(+) channel 1 (hEag1) regulates MDA-MB-231 breast cancer cell migration through Orai1-dependent calcium entry. J. Cell Physiol. 2012, 227, 3837–3846.
Tiffner, A.; Hopl, V.; Schober, R.; Sallinger, M.; Grabmayr, H.; Hoglinger, C.; Fahrner, M.; Lunz, V.; Maltan, L.; Frischauf, I.; et al. Orai1 Boosts SK3 Channel Activation. Cancers 2021, 13, 6357.
Peretti, M.; Badaoui, M.; Girault, A.; Van Gulick, L.; Mabille, M.P.; Tebbakha, R.; Sevestre, H.; Morjani, H.; Ouadid-Ahidouch, H. Original association of ion transporters mediates the ECM-induced breast cancer cell survival: Kv10.1-Orai1-SPCA2 partnership. Sci. Rep. 2019, 9, 1175.
Daya, H.A.; Kouba, S.; Ouled-Haddou, H.; Benzerdjeb, N.; Telliez, M.S.; Dayen, C.; Sevestre, H.; Garcon, L.; Hague, F.; Ouadid-Ahidouch, H. Orai3-Mediates Cisplatin-Resistance in Non-Small Cell Lung Cancer Cells by Enriching Cancer Stem Cell Population through PI3K/AKT Pathway. Cancers 2021, 13, 2314.
Terrie, E.; Deliot, N.; Benzidane, Y.; Harnois, T.; Cousin, L.; Bois, P.; Oliver, L.; Arnault, P.; Vallette, F.; Constantin, B.; et al. Store-Operated Calcium Channels Control Proliferation and Self-Renewal of Cancer Stem Cells from Glioblastoma. Cancers 2021, 13, 3428.
Schmidt, S.; Liu, G.; Liu, G.; Yang, W.; Honisch, S.; Pantelakos, S.; Stournaras, C.; Honig, A.; Lang, F. Enhanced Orai1 and STIM1 expression as well as store operated Ca2+ entry in therapy resistant ovary carcinoma cells. Oncotarget 2014, 5, 4799–4810.
Flourakis, M.; Lehen’kyi, V.; Beck, B.; Raphael, M.; Vandenberghe, M.; Abeele, F.V.; Roudbaraki, M.; Lepage, G.; Mauroy, B.; Romanin, C.; et al. Orai1 contributes to the establishment of an apoptosis-resistant phenotype in prostate cancer cells. Cell Death Dis. 2010, 1, e75.
Faouzi, M.; Kischel, P.; Hague, F.; Ahidouch, A.; Benzerdjeb, N.; Sevestre, H.; Penner, R.; Ouadid-Ahidouch, H. ORAI3 silencing alters cell proliferation and cell cycle progression via c-myc pathway in breast cancer cells. Biochim. Biophys. Acta 2013, 1833, 752–760.

© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.

Upload a video for this entry

Information

Subjects: Physiology; Cell Biology

Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :

Isaac Jardin

José Lopez

José Sánchez Collado

Juan Antonio Rosado

View Times: 437

Update Date: 29 Apr 2022

Table of Contents

Video Upload Options

Confirm

1. Introduction

2. Store-Operated Calcium Entry in Cancer Stem Cells and Cancer Hallmarks

3. Functional Role of Orai in Cancer Stem Cells and Cancer Hallmarks

References