Store-independent Orai1-mediated Ca2+ entry and cancer

Cantonero, Carlos; Sánchez-Collado, José; González-Núñez, María; Salido, Ginés M.; López, José J.; Jardín, Isaac; Rosado, Juan A.

doi:10.1016/j.ceca.2019.02.012

Cited by 31 publications

(34 citation statements)

References 94 publications

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“…Phosphorylation of Orai1 at any of these serine residues was demonstrated to result in Orai1 channel inactivation and reduction of Ca 2+ influx. These three serines are located in the Orai1 AC8-binding sequence (amino acids [26][27][28][29][30][31][32][33][34]. Here, we show that AC8 binding to Orai1 attenuates Orai1 serine phosphorylation in MDA-MB-231 cells, leading to enhanced Ca 2+ entry through the channel.…”

Section: Discussionmentioning

confidence: 61%

“…Furthermore, Orai1 is involved in store-independent Ca 2+ influx through a functional interaction with Kv10.1 potassium channels that mediate serum-induced migration [9]. Orai1 Ca 2+ channels play an important functional role in breast cancer cells supporting a number of cancer hallmarks such as migration, proliferation, or survival [33][34][35].…”

Section: Discussionmentioning

confidence: 99%

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Adenylyl Cyclase Type 8 Overexpression Impairs Phosphorylation-Dependent Orai1 Inactivation and Promotes Migration in MDA-MB-231 Breast Cancer Cells

Sánchez-Collado

López

Jardín

et al. 2019

Cancers

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Orai1 plays a major role in store-operated Ca 2+ entry (SOCE) in triple-negative breast cancer (TNBC) cells. This channel is inactivated via different mechanisms, including protein kinase C (PKC) and protein kinase A (PKA)-dependent phosphorylation at Ser-27 and Ser-30 or Ser-34, respectively, which shapes the Ca 2+ responses to agonists. The Ca 2+ calmodulin-activated adenylyl cyclase type 8 (AC8) was reported to interact directly with Orai1, thus mediating a dynamic interplay between the Ca 2+ -and cyclic adenosine monophosphate (cAMP)-dependent signaling pathways.Here, we show that the breast cancer cell lines MCF7 and MDA-MB-231 exhibit enhanced expression of Orai1 and AC8 as compared to the non-tumoral breast epithelial MCF10A cell line. In these cells, AC8 interacts with the Orai1α variant in a manner that is not regulated by Orai1 phosphorylation. AC8 knockdown in MDA-MB-231 cells, using two different small interfering RNAs (siRNAs), attenuates thapsigargin (TG)-induced Ca 2+ entry and also Ca 2+ influx mediated by co-expression of Orai1 and the Orai1-activating small fragment (OASF) of STIM1 (stromal interaction molecule-1). Conversely, AC8 overexpression enhances SOCE, as well as Ca 2+ entry, in cells co-expressing Orai1 and OASF. In MDA-MB-231 cells, we found that AC8 overexpression reduces the Orai1 phosphoserine content, thus suggesting that AC8 interferes with Orai1 serine phosphorylation, which takes place at residues located in the AC8-binding site. Consistent with this, the subset of Orai1 associated with AC8 in naïve MDA-MB-231 cells is not phosphorylated in serine residues in contrast to the AC8-independent Orai1 subset. AC8 expression knockdown attenuates migration of MCF7 and MDA-MB-231 cells, while this maneuver has no effect in the MCF10A cell line, which is likely attributed to the low expression of AC8 in these cells. We found that AC8 is required for FAK (focal adhesion kinase) phosphorylation in MDA-MB-231 cells, which might explain its role in cell migration. Finally, we found that AC8 is required for TNBC cell proliferation. These findings indicate that overexpression of AC8 in breast cancer MDA-MB-231 cells impairs the phosphorylation-dependent Orai1 inactivation, a mechanism that might support the enhanced ability of these cells to migrate.

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Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Adenylyl Cyclase Type 8 Overexpression Impairs Phosphorylation-Dependent Orai1 Inactivation and Promotes Migration in MDA-MB-231 Breast Cancer Cells

Sánchez-Collado

López

Jardín

et al. 2019

Cancers

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“…In fact, several cancer cell lines present altered [Ca 2+ ] c due to dysregulation of Ca 2+ entry mechanisms, among others [3,[5][6][7][8][9]. The Ca 2+ currents I SOC , I CRAC , and I ARC were described as relevant inward Ca 2+ currents in non-excitable cells including several cancer cell types [10,11]. I ARC involves the participation of Orai1α, Orai3, and STIM1, and in several cell types such as HEK293 cells and lymphocytes, the arachidonate-regulated Ca 2+ -selective (ARC) channel conductivity was described to be enhanced by adding low concentrations of arachidonic acid (AA) to the extracellular medium [10,[12][13][14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Arachidonic Acid Attenuates Cell Proliferation, Migration and Viability by a Mechanism Independent on Calcium Entry

Cantonero

Sánchez-Collado

López

et al. 2020

IJMS

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Arachidonic acid (AA) is a phospholipase A2 metabolite that has been reported to mediate a plethora of cellular mechanisms involved in healthy and pathological states such as platelet aggregation, lymphocyte activation, and tissue inflammation. AA has been described to activate Ca2+ entry through the arachidonate-regulated Ca2+-selective channels (ARC channels). Here, the analysis of the changes in the intracellular Ca2+ homeostasis revealed that, despite MDA-MB-231 cells expressing the ARC channel components Orai1, Orai3, and STIM1, AA does not evoke Ca2+ entry in these cells. We observed that AA evokes Ca2+ entry in MDA-MB-231 cells transiently expressing ARC channels. Nevertheless, MDA-MB-231 cell treatment with AA reduces cell proliferation and migration while inducing cell death through apoptosis. The latter mostly likely occurs via mitochondria membrane depolarization and the activation of caspases-3, -8, and -9. Altogether, our results indicate that AA exerts anti-tumoral effects on MDA-MB-231 cells, without having any effect on non-tumoral breast epithelial cells, by a mechanism that is independent on the activation of Ca2+ influx via ARC channels.

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“…In addition to the ATPase-dependent activity required for sequestering Ca 2+ and Mn 2+ ions into Golgi and vesicular stores, SPCA2 moonlights as a chaperone and activator of the Orai1 channel through interactions of its non-catalytic N-and C-terminal domains, to elicit robust Ca 2+ influx at the plasma membrane [14][15][16] . This mechanism is termed store independent Ca 2+ entry (SICE) to distinguish it from store operated Ca 2+ entry (SOCE) that occurs only upon depletion of endoplasmic reticulum Ca 2+ stores 17 . The coordinated expression of Ca 2+ transporters and activation of basal to apical Ca 2+ flux in the mammary gland epithelium is physiologically important for the accumulation of calcium in milk 12 .…”

Section: Introductionmentioning

confidence: 99%

Store Independent Ca²⁺Entry Regulates the DNA Damage Response in Breast Cancer Cells

Makena

Mekile

et al. 2020

Preprint

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Although the mainstay of treatment for hormone responsive breast tumors is targeted endocrine therapy, many patients develop de novo or acquired resistance and are treated with chemotherapeutic drugs. The vast majority (80%) of estrogen receptor positive tumors also express wild type p53 protein that is a major determinant of the DNA damage response. Tumors that are ER+ and p53 WT respond poorly to chemotherapy, although the underlying mechanisms are not completely understood. We describe a novel link between store independent Ca 2+ entry (SICE) and resistance to DNA damaging drugs, mediated by the secretory pathway Ca 2+ -ATPase, SPCA2. In luminal ER+/PR+ breast cancer subtypes, SPCA2 levels are high and correlate with poor survival prognosis. Independent of ion pump activity, SPCA2 elevates baseline Ca 2+ levels through SICE and drives cell proliferation. Attenuation of SPCA2 or depletion of extracellular Ca 2+ increased mitochondrial ROS production, DNA damage and activation of the ATM/ATR-p53 axis leading to G0/G1 phase cell cycle arrest and apoptosis. Consistent with these findings, SPCA2 knockdown confers chemosensitivity to DNA damaging agents including doxorubicin, cisplatin and ionizing radiation. We conclude that elevated SPCA2 expression in ER+ p53 WT breast tumors drives pro-survival and chemotherapy resistance by suppressing the DNA damage response. Drugs that target storeindependent Ca 2+ entry pathways may have therapeutic potential in treating receptor positive breast cancer.

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Store-independent Orai1-mediated Ca2+ entry and cancer

Cited by 31 publications

References 94 publications

Adenylyl Cyclase Type 8 Overexpression Impairs Phosphorylation-Dependent Orai1 Inactivation and Promotes Migration in MDA-MB-231 Breast Cancer Cells

Adenylyl Cyclase Type 8 Overexpression Impairs Phosphorylation-Dependent Orai1 Inactivation and Promotes Migration in MDA-MB-231 Breast Cancer Cells

Arachidonic Acid Attenuates Cell Proliferation, Migration and Viability by a Mechanism Independent on Calcium Entry

Store Independent Ca²⁺Entry Regulates the DNA Damage Response in Breast Cancer Cells

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Store-independent Orai1-mediated Ca2+ entry and cancer

Cited by 31 publications

References 94 publications

Adenylyl Cyclase Type 8 Overexpression Impairs Phosphorylation-Dependent Orai1 Inactivation and Promotes Migration in MDA-MB-231 Breast Cancer Cells

Adenylyl Cyclase Type 8 Overexpression Impairs Phosphorylation-Dependent Orai1 Inactivation and Promotes Migration in MDA-MB-231 Breast Cancer Cells

Arachidonic Acid Attenuates Cell Proliferation, Migration and Viability by a Mechanism Independent on Calcium Entry

Store Independent Ca2+Entry Regulates the DNA Damage Response in Breast Cancer Cells

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Store Independent Ca²⁺Entry Regulates the DNA Damage Response in Breast Cancer Cells