Calcium homeostasis and cancer: insights from endoplasmic reticulum-centered organelle communications

The dysregulation of calcium ion (Ca2+) homeostasis is an emerging feature of cancer and plays essential roles in the initiation and progression of malignant diseases.Endoplasmic reticulum, a major intracellular Ca2+ store, modulates Ca2+ homeostasis in coordination with other intracellular organelles, such as mitochondria and lysosomes.Cancer cells establish cancer hallmarks by altering the expression and activity of Ca2+ modulators (Ca2+ pumps, channels, and exchangers).The cancer-driven events mediated by the activation of oncogenes or inhibition of tumor suppressors are closely associated with key Ca2+ handling toolkits.Ca2+ homeostasis has become an attractive target for the development of novel anticancer drugs. Calcium ion (Ca2+) is a ubiquitous and versatile signaling molecule controlling a wide variety of cellular processes, such as proliferation, cell death, migration, and immune response, all fundamental processes essential for the establishment of cancer. In recent decades, the loss of Ca2+ homeostasis has been considered an important driving force in the initiation and progression of malignant diseases. The primary intracellular Ca2+ store, the endoplasmic reticulum (ER), plays an essential role in maintaining Ca2+ homeostasis by coordinating with other organelles and the plasma membrane. Here, we discuss the dysregulation of ER-centered Ca2+ homeostasis in cancer, summarize Ca2+-based anticancer therapeutics, and highlight the significance of furthering our understanding of Ca2+ homeostasis regulation in cancer. Calcium ion (Ca2+) is a ubiquitous and versatile signaling molecule controlling a wide variety of cellular processes, such as proliferation, cell death, migration, and immune response, all fundamental processes essential for the establishment of cancer. In recent decades, the loss of Ca2+ homeostasis has been considered an important driving force in the initiation and progression of malignant diseases. The primary intracellular Ca2+ store, the endoplasmic reticulum (ER), plays an essential role in maintaining Ca2+ homeostasis by coordinating with other organelles and the plasma membrane. Here, we discuss the dysregulation of ER-centered Ca2+ homeostasis in cancer, summarize Ca2+-based anticancer therapeutics, and highlight the significance of furthering our understanding of Ca2+ homeostasis regulation in cancer. Calcium ion (Ca2+) serves as a universal secondary messenger, involved in diverse biological processes such as proliferation, cell death, migration, and immune response [1.Giorgi C. et al.Calcium dynamics as a machine for decoding signals.Trends Cell Biol. 2018; 28: 258-273Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar]. Despite changes of Ca2+ regulation in cancer having been recognized for a long time, this area of research has only recently gained traction [2.Monteith G.R. et al.The calcium-cancer signalling nexus.Nat. Rev. Cancer. 2017; 17: 367-380Crossref PubMed Scopus (326) Google Scholar]. Accumulating evidence now demonstrates that dysregulated Ca2+ homeostasis is an essential driver of cancer initiation and progression and also influences the treatment responses of cancer patients [3.Marchi S. et al.Ca fluxes and cancer.Mol. Cell. 2020; 78: 1055-1069Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar]. The increased interest in this field is attributed to our in-depth understanding of the cellular mechanisms responsible for achieving Ca2+ homeostasis, as well as the successful application of specific Ca2+ signal-targeted therapies, for example, in cardiovascular and neuronal diseases [4.Lei M. et al.Modernized classification of cardiac antiarrhythmic drugs.Circulation. 2018; 138: 1879-1896Crossref PubMed Scopus (129) Google Scholar,5.Tiscione S.A. et al.IPR-driven increases in mitochondrial Ca promote neuronal death in NPC disease.Proc. Natl. Acad. Sci. U. S. A. 2021; 118e2110629118Crossref PubMed Scopus (17) Google Scholar]. Consequently, Ca2+ signaling has become a highly attractive target for the development of novel anticancer drugs [6.Cui C. et al.Targeting calcium signaling in cancer therapy.Acta Pharm. Sin. B. 2017; 7: 3-17Crossref PubMed Scopus (360) Google Scholar]. Playing an essential role in cell fate regulation, it is not surprising that Ca2+ signaling is rigorously regulated by a complex set of components, including Ca2+ pumps, channels, and exchangers [2.Monteith G.R. et al.The calcium-cancer signalling nexus.Nat. Rev. Cancer. 2017; 17: 367-380Crossref PubMed Scopus (326) Google Scholar]. These Ca2+-regulating 'toolkits' are distributed at plasma or intracellular organelle membranes, acting to maintain a low concentration of cytosolic free Ca2 against steep gradients of extracellular and organelle sequestered Ca2+. The ER is the primary site of Ca2+ storage [1.Giorgi C. et al.Calcium dynamics as a machine for decoding signals.Trends Cell Biol. 2018; 28: 258-273Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar], along with additional stores like the Golgi and, more recently, lysosomes [7.Vandecaetsbeek I. et al.The Ca2+ pumps of the endoplasmic reticulum and Golgi apparatus.Cold Spring Harb. Perspect. Biol. 2011; 3a004184Crossref PubMed Scopus (162) Google Scholar,8.Wu Y. et al.Lysosomal calcium channels in autophagy and cancer.Cancers (Basel). 2021; 13: 1299Crossref PubMed Scopus (20) Google Scholar]. The Ca2+ concentration within mitochondria is relatively low under resting conditions. Nonetheless, upon activation by diverse stimuli or signaling events, almost all organelles are involved in orchestrating a complex response in order to maintain Ca2+ homeostasis or transmit Ca2+ signal [1.Giorgi C. et al.Calcium dynamics as a machine for decoding signals.Trends Cell Biol. 2018; 28: 258-273Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar]. As the major Ca2+ store, the ER is central to such a response. The regulation of Ca2+ homeostasis and Ca2+ signaling has been extensively reviewed elsewhere [2.Monteith G.R. et al.The calcium-cancer signalling nexus.Nat. Rev. Cancer. 2017; 17: 367-380Crossref PubMed Scopus (326) Google Scholar,3.Marchi S. et al.Ca fluxes and cancer.Mol. Cell. 2020; 78: 1055-1069Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar]. Here, we focus on our recent understanding of ER-centered Ca2+ homeostasis regulation and its association with cancer. The ER plays a central role in protein and lipid synthesis and is also the largest intracellular Ca2+ reservoir [9.Raffaello A. et al.Calcium at the center of cell signaling: interplay between endoplasmic reticulum, mitochondria, and lysosomes.Trends Biochem. Sci. 2016; 41: 1035-1049Abstract Full Text Full Text PDF PubMed Scopus (316) Google Scholar]. The high Ca2+ concentration provides the optimal environment for the activity of local enzymes required for physiological functions of the ER, whilst contributing to the maintenance of low cytosolic Ca2+ under resting conditions. Upon stimulus, the ER releases Ca2+, which facilitates the rapid transmission of Ca2+ signals, leading to distinctive biological outcomes, such as proliferation and cell death [1.Giorgi C. et al.Calcium dynamics as a machine for decoding signals.Trends Cell Biol. 2018; 28: 258-273Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar,3.Marchi S. et al.Ca fluxes and cancer.Mol. Cell. 2020; 78: 1055-1069Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar]. ER Ca2+ homeostasis is determined by a finely tuned balance of Ca2+ influx and outflux. Sarcoplasmic-endoplasmic type ATPases (SERCAs) (see Glossary), the ER-resident Ca2+ pumps, are responsible for ER Ca2+ influx [9.Raffaello A. et al.Calcium at the center of cell signaling: interplay between endoplasmic reticulum, mitochondria, and lysosomes.Trends Biochem. Sci. 2016; 41: 1035-1049Abstract Full Text Full Text PDF PubMed Scopus (316) Google Scholar]. Whereas Ca2+ outflux is mediated by Ca2+ channels, such as inositol 1,4,5-trisphosphate receptors (IP3Rs), in response to the enhanced IP3 upon hormone or growth factor stimulation [9.Raffaello A. et al.Calcium at the center of cell signaling: interplay between endoplasmic reticulum, mitochondria, and lysosomes.Trends Biochem. Sci. 2016; 41: 1035-1049Abstract Full Text Full Text PDF PubMed Scopus (316) Google Scholar], or ryanodine receptors (RyRs), in response to extracellular Ca2+ influx [9.Raffaello A. et al.Calcium at the center of cell signaling: interplay between endoplasmic reticulum, mitochondria, and lysosomes.Trends Biochem. Sci. 2016; 41: 1035-1049Abstract Full Text Full Text PDF PubMed Scopus (316) Google Scholar]. The latter process is known as Ca2+-induced Ca2+ release (CICR) [9.Raffaello A. et al.Calcium at the center of cell signaling: interplay between endoplasmic reticulum, mitochondria, and lysosomes.Trends Biochem. Sci. 2016; 41: 1035-1049Abstract Full Text Full Text PDF PubMed Scopus (316) Google Scholar]. In response to a reduction in Ca2+ concentration, the ER-resident transmembrane protein, stromal interaction molecule 1 (STIM1), is activated, which interacts with and activates the calcium release-activated calcium modulator 1 (ORAI1) channel, localized in the plasma membrane, leading to extracellular Ca2+ influx and the subsequent SERCA2-mediated ER Ca2+ refilling, a process named store operated Ca2+ entry (SOCE) [9.Raffaello A. et al.Calcium at the center of cell signaling: interplay between endoplasmic reticulum, mitochondria, and lysosomes.Trends Biochem. Sci. 2016; 41: 1035-1049Abstract Full Text Full Text PDF PubMed Scopus (316) Google Scholar]. The transmembrane and coiled-coil domains 1 (TMCO1) transmembrane protein, localized within the ER, controls how cells restore ER homeostasis in the case of Ca2+ overload. TMCO1 is present as an inactive monomer under resting conditions. During ER Ca2+ overload, it forms a selective Ca2+ channel through monomer-to-tetramer transformation, leading to ER Ca2+ homeostasis recovery, a process known as store overload-induced Ca2+ release (SOICR) [10.Wang Q.-C. et al.TMCO1 is an ER Ca2+ load-activated Ca2+ channel.Cell. 2016; 165: 1454-1466Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar] (Figure 1A ). Enhanced cytosolic Ca2+, sourced from either the extracellular space or the ER, can trigger mitochondrial Ca2+ uptake [1.Giorgi C. et al.Calcium dynamics as a machine for decoding signals.Trends Cell Biol. 2018; 28: 258-273Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar]. The latest evidence has demonstrated that the two distinct organelles, the ER and mitochondria, are physiologically and functionally connected at multiple sites [called mitochondria-associated ER membrane (MAM)] involved in various biological processes, including regulating Ca2+ homeostasis [1.Giorgi C. et al.Calcium dynamics as a machine for decoding signals.Trends Cell Biol. 2018; 28: 258-273Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar]. Mechanistically, IP3Rs and voltage-dependent anion channels (VDACs) form a complex spanning the MAM, promoting mitochondrial Ca2+ uptake in the outer mitochondrial membrane [9.Raffaello A. et al.Calcium at the center of cell signaling: interplay between endoplasmic reticulum, mitochondria, and lysosomes.Trends Biochem. Sci. 2016; 41: 1035-1049Abstract Full Text Full Text PDF PubMed Scopus (316) Google Scholar]. In contrast, the Ca2+ influx through the inner mitochondrial membrane is mainly driven by a negative membrane potential (ΔΨm: ~–180mV) and Ca2+ gradient through the mitochondrial calcium uniporter (MCU) [1.Giorgi C. et al.Calcium dynamics as a machine for decoding signals.Trends Cell Biol. 2018; 28: 258-273Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar] (Figure 1B). Lysosomes are typically considered as organelles that deal with intracellular waste. They are now known to be significant Ca2+ stores, acting as functional hubs in regulating Ca2+ homeostasis along with the ER [8.Wu Y. et al.Lysosomal calcium channels in autophagy and cancer.Cancers (Basel). 2021; 13: 1299Crossref PubMed Scopus (20) Google Scholar]. An increase in local cytosolic Ca2+ at the ER–lysosome interface sensitizes IP3R, thus evoking Ca2+ transport from the ER to lysosome [8.Wu Y. et al.Lysosomal calcium channels in autophagy and cancer.Cancers (Basel). 2021; 13: 1299Crossref PubMed Scopus (20) Google Scholar]. The activation of nicotinic acid adenine dinucleotide phosphate (NAADP)-regulated two-pore channels (TPCs) [11.Marchant J.S. et al.NAADP-binding proteins find their identity.Trends Biochem. Sci. 2022; 47: 235-249Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar] or mucolipin (MCOLN) family of transient receptor potential (TRPML) [12.Rosato A.S. et al.Two-pore and TRPML cation channels: regulators of phagocytosis, autophagy and lysosomal exocytosis.Pharmacol. Ther. 2021; 220107713Crossref PubMed Scopus (19) Google Scholar] on lysosomes can elicit a local ER Ca2+ release in a process similar to CICR [13.Capel R.A. et al.Two-pore channels (TPC2s) and nicotinic acid adenine dinucleotide phosphate (NAADP) at lysosomal-sarcoplasmic reticular junctions contribute to acute and chronic β-adrenoceptor signaling in the heart.J. Biol. Chem. 2015; 290: 30087-30098Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar] (Figure 1C). The ER coordinates with other organelles in maintaining Ca2+ homeostasis (Figure 1). Upon stimulation, Ca2+ signal is activated and the subsequent biological outcomes are determined by the magnitude, frequency, and localization of Ca2+ flux, processes linked to carcinogenesis. Given their key roles in Ca2+ homeostasis, the expression and activity of Ca2+ pumps, channels, and exchangers are frequently altered in human cancers [3.Marchi S. et al.Ca fluxes and cancer.Mol. Cell. 2020; 78: 1055-1069Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar]. Table S1 (in the supplemental information online) provides a summary of differential isoform expression and cancer type-specific dysregulation of Ca2+ homeostasis. This dysregulation in turn leads to increased cell proliferation, migration, resistance to apoptosis, and immune evasion, which are discussed in further detail later. Under physiological conditions, Ca2+ signaling is controlled in a cell cycle-dependent manner. Some IP3R family members have been linked to cell senescence [14.Wiel C. et al.Endoplasmic reticulum calcium release through ITPR2 channels leads to mitochondrial calcium accumulation and senescence.Nat. Commun. 2014; 5: 3792Crossref PubMed Scopus (132) Google Scholar,15.Ziegler D.V. et al.Calcium channel ITPR2 and mitochondria-ER contacts promote cellular senescence and aging.Nat. Commun. 2021; 12: 720Crossref PubMed Scopus (54) Google Scholar]. Although it remains to be determined whether these mechanisms directly confer carcinogenesis sensitivity, IP3R knockout in thymocytes was found to decrease proliferation and suppress the development of acute lymphoblastic leukemia [16.Ouyang K. et al.Loss of IP3R-dependent Ca2+ signalling in thymocytes leads to aberrant development and acute lymphoblastic leukemia.Nat. Commun. 2014; 5: 4814Crossref PubMed Scopus (49) Google Scholar]. Among the three IP3R family proteins, IP3R3 expression is frequently upregulated in cancers (Table S1 in the supplemental information online). Genetic or pharmacological inhibition of IP3R3 significantly reduces cancer cell proliferation [17.Szatkowski C. et al.Inositol 1,4,5-trisphosphate-induced Ca2+ signalling is involved in estradiol-induced breast cancer epithelial cell growth.Mol. Cancer. 2010; 9: 156Crossref PubMed Scopus (70) Google Scholar, 18.Guerra M.T. et al.Expression of the type 3 InsP receptor is a final common event in the development of hepatocellular carcinoma.Gut. 2019; 68: 1676-1687Crossref PubMed Scopus (54) Google Scholar, 19.Ueasilamongkol P. et al.Type 3 inositol 1,4,5-trisphosphate receptor is increased and enhances malignant properties in cholangiocarcinoma.Hepatology. 2020; 71: 583-599Crossref PubMed Scopus (42) Google Scholar], implying IP3R3 is a potential therapeutic target to reduce cancer cell growth. The association between SOCE and proliferation has also been established. A potent SOCE inhibitor, RP4010, produces a dramatic antiproliferation effect by inducing G0/G1 arrest in esophageal cancer [20.Cui C. et al.Targeting Orai1-mediated store-operated calcium entry by RP4010 for anti-tumor activity in esophagus squamous cell carcinoma.Cancer Lett. 2018; 432: 169-179Crossref PubMed Scopus (30) Google Scholar]. Whereas knocking down STIM1 in cervical cancer cells arrests cell cycle progression at S and G2/M phases [21.Chen Y.-F. et al.Calcium store sensor stromal-interaction molecule 1-dependent signaling plays an important role in cervical cancer growth, migration, and angiogenesis.Proc. Natl. Acad. Sci. U. S. A. 2011; 108: 15225-15230Crossref PubMed Scopus (280) Google Scholar], suggesting that the SOCE components may act by controlling distinct cell cycle checkpoints, in a context-dependent manner. The low-level, constitutive Ca2+ transfer from ER to mitochondria is critical for cancer cell survival and proliferation [22.Cárdenas C. et al.Selective vulnerability of cancer cells by inhibition of Ca2+ transfer from endoplasmic reticulum to mitochondria.Cell Rep. 2016; 14: 2313-2324Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar,23.Zhao H. et al.AMPK-mediated activation of MCU stimulates mitochondrial Ca entry to promote mitotic progression.Nat. Cell Biol. 2019; 21: 476-486Crossref PubMed Scopus (85) Google Scholar]. Mitochondrial Ca2+ accumulation activates Ca2+-sensitive dehydrogenases of the tricarboxylic acid cycle and is thus critical for the biosynthetic and bioenergetic needs of cancer cells [23.Zhao H. et al.AMPK-mediated activation of MCU stimulates mitochondrial Ca entry to promote mitotic progression.Nat. Cell Biol. 2019; 21: 476-486Crossref PubMed Scopus (85) Google Scholar,24.Young M.P. et al.Metabolic adaptation to the chronic loss of Ca signaling induced by KO of IP receptors or the mitochondrial Ca uniporter.J. Biol. Chem. 2022; 298101436Abstract Full Text Full Text PDF Scopus (7) Google Scholar]. The involvement of MAM in regulating cell proliferation is exemplified by ER-resident IP3R (as discussed earlier) and additionally by mitochondrial VDAC1 in lung cancer [25.Arif T. et al.Silencing VDAC1 expression by siRNA inhibits cancer cell proliferation and tumor growth in vivo.Mol. Ther. Nucleic Acids. 2014; 3e159Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar] and the MCU in colorectal cancer [26.Liu Y. et al.MCU-induced mitochondrial calcium uptake promotes mitochondrial biogenesis and colorectal cancer growth.Signal Transduct. Target. Ther. 2020; 5: 59Crossref PubMed Scopus (54) Google Scholar,27.Zeng F. et al.RIPK1 binds MCU to mediate induction of mitochondrial Ca uptake and promotes colorectal oncogenesis.Cancer Res. 2018; 78: 2876-2885Crossref PubMed Scopus (56) Google Scholar]. Dysregulated Ca2+ homeostasis has been shown to promote cell proliferation with a high energy expenditure, which provides potential vulnerable targets in cancer cells under metabolic stress [24.Young M.P. et al.Metabolic adaptation to the chronic loss of Ca signaling induced by KO of IP receptors or the mitochondrial Ca uniporter.J. Biol. Chem. 2022; 298101436Abstract Full Text Full Text PDF Scopus (7) Google Scholar,28.Cardenas C. et al.Cancer cells with defective oxidative phosphorylation require endoplasmic reticulum-to-mitochondria Ca transfer for survival.Sci. Signal. 2020; 13: eaay1212Crossref PubMed Scopus (39) Google Scholar]. A moderate Ca2+ signal is essential for cell proliferation, while massive cytosolic Ca2+ influx or mitochondria Ca2+ overload triggers cell death [29.Loncke J. et al.Balancing ER-mitochondrial Ca fluxes in health and disease.Trends Cell Biol. 2021; 31: 598-612Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar]. SERCAs have been recently shown to protect cancer stem cells (CSCs) from glucose starvation-induced apoptosis by limiting cytosolic Ca2+ sourced from the ER [30.Park K.C. et al.Survival of cancer stem-like cells under metabolic stress via CaMK2α-mediated upregulation of sarco/endoplasmic reticulum calcium ATPase expression.Clin. Cancer Res. 2018; 24: 1677-1690Crossref PubMed Scopus (26) Google Scholar]. We have reported that the SOICR channel protein TMCO1 promotes tumor growth and protects colon cancer cells from staurosporine-induced apoptosis, by limiting cytosolic Ca2+ dynamics [31.Zheng S. et al.iASPP suppresses Gp78-mediated TMCO1 degradation to maintain Ca homeostasis and control tumor growth and drug resistance.Proc. Natl. Acad. Sci. U. S. A. 2022; 119e2111380119Crossref Scopus (6) Google Scholar]. Another study reported that TMCO1 inhibits tumor growth in urinary bladder urothelial carcinoma, but whether this effect is related to its ER Ca2+ regulatory activity remains to be determined [32.Li C.-F. et al.Transmembrane and coiled-coil domain 1 impairs the AKT signaling pathway in urinary bladder urothelial carcinoma: a characterization of a tumor suppressor.Clin. Cancer Res. 2017; 23: 7650-7663Crossref PubMed Scopus (21) Google Scholar]. It is possible that TMCO1 has a Ca2+-independent function, or it acts differentially in cancer cells in a context-dependent manner. Undoubtedly, researching the actions of TMCO1 in additional cancer cells will further guide TMCO1-targeted anticancer therapies. Increased Ca2+ influx mediated by SOCE is another trigger of cytosolic Ca2+-induced apoptosis. Loss of STIM1 has been shown to abolish cisplatin-induced apoptosis in non-small cell lung carcinoma cells [33.Gualdani R. et al.Store-operated calcium entry contributes to cisplatin-induced cell death in non-small cell lung carcinoma.Cancers (Basel). 2019; 11: 430Crossref PubMed Scopus (32) Google Scholar]. Similar effect of ORAI1 was also detected in prostate cancer cells treated with thapsigargin (TG), tumor necrosis factor α (TNF-α), and cisplatin/oxaliplatin [34.Flourakis M. et al.Orai1 contributes to the establishment of an apoptosis-resistant phenotype in prostate cancer cells.Cell Death Dis. 2010; 1e75Crossref PubMed Scopus (171) Google Scholar]. At the MAM, IP3R and VDAC isoforms act in stimulus and context-dependent ways. Increased IP3R3 expression or activities [18.Guerra M.T. et al.Expression of the type 3 InsP receptor is a final common event in the development of hepatocellular carcinoma.Gut. 2019; 68: 1676-1687Crossref PubMed Scopus (54) Google Scholar,35.Liao C. et al.Identification of BBOX1 as a therapeutic target in triple-negative breast cancer.Cancer Discov. 2020; 10: 1706-1721Crossref PubMed Scopus (26) Google Scholar] induces proliferation as well as apoptosis resistance in multiple cancer cells. Paradoxically, IP3R3 elicits proapoptotic effects in ovarian and lung cancer cells, resulting in cisplatin sensibility by enhancing Ca2+ transfer from the ER to mitochondria [36.Xue Y. et al.SMARCA4/2 loss inhibits chemotherapy-induced apoptosis by restricting IP3R3-mediated Ca flux to mitochondria.Nat. Commun. 2021; 12: 5404Crossref PubMed Scopus (12) Google Scholar]. Additionally, anti- and proapoptotic functions of IP3Rs have been assigned to IP3R3 and IP3R1, respectively, in the same cancer context [37.Rezuchova I. et al.Type 3 inositol 1,4,5-trisphosphate receptor has antiapoptotic and proliferative role in cancer cells.Cell Death Dis. 2019; 10: 186Crossref PubMed Scopus (46) Google Scholar]. Why IP3R isoforms produce such diverse functional outcomes still needs to be further explored. Similarly, VDAC1 promotes apoptosis by facilitating mitochondrial Ca2+ influx [38.De Stefani D. et al.VDAC1 selectively transfers apoptotic Ca2+ signals to mitochondria.Cell Death Differ. 2012; 19: 267-273Crossref PubMed Scopus (230) Google Scholar], while VDAC2 protects cells from apoptosis, possibly independently of Ca2+ signal transmission [38.De Stefani D. et al.VDAC1 selectively transfers apoptotic Ca2+ signals to mitochondria.Cell Death Differ. 2012; 19: 267-273Crossref PubMed Scopus (230) Google Scholar]. In line with this finding, inhibition of ER-to-mitochondria Ca2+ transfer has recently been proposed as a general strategy to target apoptosis in cancer cells [28.Cardenas C. et al.Cancer cells with defective oxidative phosphorylation require endoplasmic reticulum-to-mitochondria Ca transfer for survival.Sci. Signal. 2020; 13: eaay1212Crossref PubMed Scopus (39) Google Scholar]. Metastasis is a complex multistep process, which accounts for more than 90% of cancer mortality [39.Wang J.Y. et al.STIM1 overexpression promotes colorectal cancer progression, cell motility and COX-2 expression.Oncogene. 2015; 34: 4358-4367Crossref PubMed Scopus (107) Google Scholar]. The overexpression of SOCE components is associated with poor outcomes in patients with colorectal cancer [39.Wang J.Y. et al.STIM1 overexpression promotes colorectal cancer progression, cell motility and COX-2 expression.Oncogene. 2015; 34: 4358-4367Crossref PubMed Scopus (107) Google Scholar]. Consistently, STIM1- and ORAI1-mediated Ca2+ oscillations promote cancer cell invasion by orchestrating invadopodium assembly and extracellular matrix (ECM) degradation [40.Sun J. et al.STIM1- and Orai1-mediated Ca2+ oscillation orchestrates invadopodium formation and melanoma invasion.J. Cell Biol. 2014; 207: 535-548Crossref PubMed Scopus (123) Google Scholar]. SOCE blockade inhibits metastasis in vivo and in vitro [40.Sun J. et al.STIM1- and Orai1-mediated Ca2+ oscillation orchestrates invadopodium formation and melanoma invasion.J. Cell Biol. 2014; 207: 535-548Crossref PubMed Scopus (123) Google Scholar,41.Lee S.K. et al.Metastasis enhancer PGRMC1 boosts store-operated Ca entry by uncoiling Ca sensor STIM1 for focal adhesion turnover and actomyosin formation.Cell Rep. 2022; 38110281Abstract Full Text Full Text PDF Scopus (8) Google Scholar]. Ca2+ flux at the MAM may also affect cancer metastasis, for example, VDAC1 promotes reactive oxygen species (ROS) production in lung cancer cells [25.Arif T. et al.Silencing VDAC1 expression by siRNA inhibits cancer cell proliferation and tumor growth in vivo.Mol. Ther. Nucleic Acids. 2014; 3e159Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar]. Conversely, the MCU promotes pancreatic ductal adenocarcinoma cell metastasis by activating the KEAP1-NRF2 antioxidant program [42.Wang X. et al.Mitochondrial calcium uniporter drives metastasis and confers a targetable cystine dependency in pancreatic cancer.Cancer Res. 2022; 82: 2254-2268Crossref PubMed Scopus (24) Google Scholar]. A variety of Ca2+ channels localized in the membrane of lysosomes have been shown to regulate invasion or migration of liver, breast, and lung cancer cells, through modulating the local and global intracellular Ca2+-mediated lysosomal exocytosis [8.Wu Y. et al.Lysosomal calcium channels in autophagy and cancer.Cancers (Basel). 2021; 13: 1299Crossref PubMed Scopus (20) Google Scholar]. Whether ER–lysosome communications are involved in these processes remains to be explored. In addition to ECM remodeling, increased metastasis has been linked to angiogenesis. STIM1 or TRPML1 is able to promote angiogenesis, which possibly contributes to the increased metastasis observed in cancer cells that overexpress STIM1 or TRPML1 [21.Chen Y.-F. et al.Calcium store sensor stromal-interaction molecule 1-dependent signaling plays an important role in cervical cancer growth, migration, and angiogenesis.Proc. Natl. Acad. Sci. U. S. A. 2011; 108: 15225-15230Crossref PubMed Scopus (280) Google Scholar]. An increase in the intracellular Ca2+ concentration is required for a variety of immune responses, for which the SOCE is essential [43.Xie J. et al.SOCE and cancer: recent progress and new perspectives.Int. J. Cancer. 2016; 138: 2067-2077Crossref PubMed Scopus (73) Google Scholar]. Defects in SOCE, caused by STIM1 or ORAI1 depletion, result in the dysfunction of a variety of immune cells [43.Xie J. et al.SOCE and cancer: recent progress and new perspectives.Int. J. Cancer. 2016; 138: 2067-2077Crossref PubMed Scopus (73) Google Scholar]. Given the essential role of immune clearance in cancer, an increasing number of studies have established the connection between SOCE-regulated immune response and carcinogenesis. For example, mice with a STIM1 conditional knockout in CD8+ T cells lose their ability to engulf melanoma and colon carcinoma cells, both in vivo and in vitro [44.Weidinger C. et al.STIM1 and STIM2-mediated Ca2+ influx regulates antitumour immunity by CD8+ T cells.EMBO Mol. Med. 2013; 5: 1311-1321Crossref PubMed Scopus (80) Google Scholar]. Alternatively, ablation of STIM1 in mouse myeloid cells impairs crosspresentation and dendritic cell (DC) migration, leading to impaired cytotoxic T cell activation and reduced cancer cell clearance [45.Nunes-Hasler P. et al.STIM1 promotes migration, phagosomal maturation and antigen cross-presentation in dendritic cells.Nat. Commun. 2017; 8: 1852Crossref PubMed Scopus (39) Google Scholar]. Recently, SERCA has been shown to regulate V(D)J recombination [46.Chen C.-C. et al.Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) activity is required for V(D)J recombination.J. Exp. Med. 2021; 218e20201708Crossref Scopus (4) Google Scholar], and IP3R influences DC activities [47.Marongiu L. et al.Inositol 1,4,5-trisphosphate 3-kinase B promotes Ca mobilization and the inflammatory activity of dendritic cells.Sci. Signal. 2021; 14: eaaz2120Crossref PubMed Scopus (15) Google Scholar]; therefore, it is likely that Ca2+ modulators are commonly involved in immune responses. However, the significance of such mechanisms in cancer immunity remains unclear. It should be noted that inhibition of glutamine