The pancreas-specific form of secretory pathway calcium ATPase 2 regulates multiple pathways involved in calcium homeostasis

Fenech, Melissa; Carter, McKenzie M.; Stathopulos, Peter B.; Pin, Christopher L.

doi:10.1016/j.bbamcr.2019.118567

Cited by 7 publications

(18 citation statements)

References 38 publications

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“…ATP2C2 is mainly expressed in salivary glands, gastrointestinal and respiratory tracts, and mammary gland, and participates in Ca 2+ transport in secretion (23). ATP2C2 has been shown to be involved in many important biological functions, such as the regulation of calcium homeostasis, and modulation of phonological short-term memory in language impairment (24,25). In addition, it was shown that ATP2C2 helps colon cancer cells adapt to hypoxia, prevents cancer cells death, increases proliferation capacity and promotes tumor growth (26).…”

Section: Discussionmentioning

confidence: 99%

ATP2C2 Has Potential to Define Tumor Microenvironment in Breast Cancer

Liu

Wei

et al. 2021

Front. Immunol.

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Tumor microenvironment (TME) is vital for the occurrence and development of breast cancer (BRCA). However, it remains challenging to understand the dynamic modulation of the stromal and immune components comprehensively in TME. Herein, we used ESTIMATE and CIBERSORT algorithm to estimate the number of stromal and immune components and the abundance of tumor-infiltrating immune cells (TICs) in 582 BRCA cases from gene expression omnibus (GEO) database. We employed three regression models including univariable Cox proportion, LASSO regression model and multivariate Cox regression, and identified 7 immune-specific genes related to BRCA survival. Of 7 genes, ATPase Secretory Pathway Ca2+ Transporting 2 (ATP2C2) attracts our attention for significantly predicting prognosis of BRCA patients. Further analysis indicated that ATP2C2 expression was closely related to the clinicopathological features (age, T- and N-staging) and negatively correlated with patients’ survival in BRCA. Gene Set Enrichment Analysis (GSEA) was performed to reveal pathway enrichment between ATP2C2high and ATP2C2low groups. The low ATP2C2 expression groups’ genes were mainly enriched for immune-related activities, while those in the ATP2C2 high-expression group were largely enriched in metabolic-related pathways. Notably, Pearson’s correlation analysis identified that ATP2C2 expression was positively correlated with T follicular helper (Tfh) cells, and negatively correlated with gamma delta (γδ) T cell, suggesting that ATP2C2 might be accountable for the maintenance of immune-dominant status for TME. To sum up, this study comprehensively analyzed the TME and shed light on prognostic immune-related biomarkers for BRCA. In particular, ATP2C2 might be helpful for predicting the prognosis of BRCA patients, which provided an extra insight for BRCA treatment.

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Section: Discussionmentioning

confidence: 99%

ATP2C2 Has Potential to Define Tumor Microenvironment in Breast Cancer

Liu

Wei

et al. 2021

Front. Immunol.

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“…SPCA2 expression increases in pregnancy, peaking during parturition, continues to be elevated during lactation for the transport and secretion of Ca 2+ into milk and returns to basal levels following involution of the mammary gland 12,13 . 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 .…”

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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“…Although the specific interaction site was not determined in the concerning study, it is plausible to assume that it also resides within the cytosolic portions of Orai1. In addition, some isoforms of the secretory pathway Ca 2+ ATPase of the Golgi apparatus have been supposed as promotors of Orai1 plasma membrane expression, but in a considerably cell type specific manner and primarily in settings where Orai1 proteins mediate store-independent Ca 2+ entry (SICE) rather than relying on STIM1 dependent activation [79][80][81][82][83].…”

Section: Internalization and Recyclingmentioning

confidence: 99%

Highlighting the Multifaceted Role of Orai1 N-Terminal- and Loop Regions for Proper CRAC Channel Functions

Humer

Romanin

Höglinger

2022

Cells

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Orai1, the Ca2+-selective pore in the plasma membrane, is one of the key components of the Ca2+release-activated Ca2+ (CRAC) channel complex. Activated by the Ca2+ sensor in the endoplasmic reticulum (ER) membrane, stromal interaction molecule 1 (STIM1), via direct interaction when ER luminal Ca2+ levels recede, Orai1 helps to maintain Ca2+ homeostasis within a cell. It has already been proven that the C-terminus of Orai1 is indispensable for channel activation. However, there is strong evidence that for CRAC channels to function properly and maintain all typical hallmarks, such as selectivity and reversal potential, additional parts of Orai1 are needed. In this review, we focus on these sites apart from the C-terminus; namely, the second loop and N-terminus of Orai1 and on their multifaceted role in the functioning of CRAC channels.

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The pancreas-specific form of secretory pathway calcium ATPase 2 regulates multiple pathways involved in calcium homeostasis

Cited by 7 publications

References 38 publications

ATP2C2 Has Potential to Define Tumor Microenvironment in Breast Cancer

ATP2C2 Has Potential to Define Tumor Microenvironment in Breast Cancer

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

Highlighting the Multifaceted Role of Orai1 N-Terminal- and Loop Regions for Proper CRAC Channel Functions

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The pancreas-specific form of secretory pathway calcium ATPase 2 regulates multiple pathways involved in calcium homeostasis

Cited by 7 publications

References 38 publications

ATP2C2 Has Potential to Define Tumor Microenvironment in Breast Cancer

ATP2C2 Has Potential to Define Tumor Microenvironment in Breast Cancer

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

Highlighting the Multifaceted Role of Orai1 N-Terminal- and Loop Regions for Proper CRAC Channel Functions

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