Orai1 Boosts SK3 Channel Activation

Tiffner, Adéla; Hopl, Valentina; Schober, Romana; Sallinger, Matthias; Grabmayr, Herwig; Höglinger, Carmen; Fahrner, Marc; Lunz, Victoria; Maltan, Lena; Frischauf, Irene; Krivić, Denis; Bhardwaj, Rajesh; Schindl, Rainer; Hediger, Matthias A.; Derler, Isabella

doi:10.3390/cancers13246357

Cited by 7 publications

(18 citation statements)

References 116 publications

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“…Similarly, colon cancer cell growth is driven by an interplay of SK3 and Orai1 which is further supported by STIM1 and TRPC1 [292]. We provided recently further indications that the SK3/Orai1 interplay also occurs in LNCaP cells and drives their proliferation [300]. Moreover, we discovered that SK3/Orai1 co-regulation can also occur in the standard overexpression cell line, HEK 293.…”

Section: Lipid-mediated Modulation Of the Co-regulation Of Crac Chann...supporting

confidence: 55%

The Role of Lipids in CRAC Channel Function

2022

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The composition and dynamics of the lipid membrane define the physical properties of the bilayer and consequently affect the function of the incorporated membrane transporters, which also applies for the prominent Ca2+ release-activated Ca2+ ion channel (CRAC). This channel is activated by receptor-induced Ca2+ store depletion of the endoplasmic reticulum (ER) and consists of two transmembrane proteins, STIM1 and Orai1. STIM1 is anchored in the ER membrane and senses changes in the ER luminal Ca2+ concentration. Orai1 is the Ca2+-selective, pore-forming CRAC channel component located in the plasma membrane (PM). Ca2+ store-depletion of the ER triggers activation of STIM1 proteins, which subsequently leads to a conformational change and oligomerization of STIM1 and its coupling to as well as activation of Orai1 channels at the ER-PM contact sites. Although STIM1 and Orai1 are sufficient for CRAC channel activation, their efficient activation and deactivation is fine-tuned by a variety of lipids and lipid- and/or ER-PM junction-dependent accessory proteins. The underlying mechanisms for lipid-mediated CRAC channel modulation as well as the still open questions, are presented in this review.

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Section: Lipid-mediated Modulation Of the Co-regulation Of Crac Chann...supporting

confidence: 55%

The Role of Lipids in CRAC Channel Function

2022

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“…SK channels, like CRAC channels, are involved in the development of diverse cancer hallmarks. Gene expression of SK channels was detected in breast cancer (SK2 and SK3) [327], glioma (SK2) [324], medulloblastoma (SK3) [328], melanoma (SK2 and SK3) [342], colon (SK3), and prostate cancer (SK3) [331,[343][344][345]. Interestingly, the detected SK transcripts do not necessarily confirm the expression of the functional protein, as reported for the SK2 gene in breast cancer and glioma [324,327].…”

Section: Sk Channels and Cancermentioning

confidence: 84%

CRAC and SK Channels: Their Molecular Mechanisms Associated with Cancer Cell Development

Tiffner

Hopl

Derler

2022

Cancers

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Cancer represents a major health burden worldwide. Several molecular targets have been discovered alongside treatments with positive clinical outcomes. However, the reoccurrence of cancer due to therapy resistance remains the primary cause of mortality. Endeavors in pinpointing new markers as molecular targets in cancer therapy are highly desired. The significance of the co-regulation of Ca2+-permeating and Ca2+-regulated ion channels in cancer cell development, proliferation, and migration make them promising molecular targets in cancer therapy. In particular, the co-regulation of the Orai1 and SK3 channels has been well-studied in breast and colon cancer cells, where it finally leads to an invasion-metastasis cascade. Nevertheless, many questions remain unanswered, such as which key molecular components determine and regulate their interplay. To provide a solid foundation for a better understanding of this ion channel co-regulation in cancer, we first shed light on the physiological role of Ca2+ and how this ion is linked to carcinogenesis. Then, we highlight the structure/function relationship of Orai1 and SK3, both individually and in concert, their role in the development of different types of cancer, and aspects that are not yet known in this context.

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“…The oscillatory Ca 2+ signaling facilitated invadopodial precursor assembly via Src activation and increased proteolytic activity of invadopodia by recruitment of ECM-degrading membrane type 1 matrix metalloproteinase (MT1-MMP) [33]. Then, Ca 2+ -activated K + channels, such as SK3, enhanced the driving force for Ca 2+ entry through hyperpolarization of resting membrane potential [34,35]. Moreover, abnormal opens of sodium ion channels also contributed to invadopodia formation via F-actin polymerization [36].…”

Section: Discussionmentioning

confidence: 99%

A bioinformatics analysis: ZFHX4 is associated with metastasis and poor survival in ovarian cancer

Zong

et al. 2022

J Ovarian Res

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Background Metastasis was the major cause of the high mortality in ovarian cancer. Although some mechanisms of metastasis in ovarian cancer were proposed, few have been targeted in the clinical practice. In the study, we aimed to identify novel genes contributing to metastasis and poor clinical outcome in ovarian cancer from bioinformatics databases. Methods Studies collecting matched primary tumors and metastases from ovarian cancer patients were searched in the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were screened by software R language. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis for the DEGs were implemented by Metascape. Venn diagram was plotted to present overlapping DEGs. The associations between the overlapping DEGs and prognosis were tested by Cox proportional hazard regression model using a cohort of ovarian cancer patients from the TCGA database. Genes affecting patients’ outcomes significantly were served as hub genes. The mechanisms of the hub genes in promoting ovarian cancer metastasis were then predicted by R software. Results Two gene expression profiles (GSE30587 and GSE73168) met the inclusion criteria and were finally analyzed. A total of 259 genes were significantly differentially expressed in GSE30587, whereas 712 genes were in GSE73168. In GSE30587, DEGs were mainly involved in extracellular matrix (ECM) organization; For GSE73168, most of DEGs showed ion trans-membrane transport activity. There were 9 overlapping genes between the two datasets (RUNX2, FABP4, CLDN20, SVEP1, FAM169A, PGM5, ZFHX4, DCN and TAS2R50). ZFHX4 was proved to be an independent adverse prognostic factor for ovarian cancer patients (HR = 1.44, 95%CI: 1.13–1.83, p = 0.003). Mechanistically, ZFHX4 was positively significantly correlated with epithelial-mesenchymal transition (EMT) markers (r = 0.54, p = 2.59 × 10−29) and ECM-related genes (r = 0.52, p = 2.86 × 10−27). Conclusions ZFHX4 might promote metastasis in ovarian cancer by regulating EMT and reprogramming ECM. For clinical applications, ZFHX4 was expected to be a prognostic biomarker for ovarian cancer metastasis.

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Orai1 Boosts SK3 Channel Activation

Cited by 7 publications

References 116 publications

The Role of Lipids in CRAC Channel Function

The Role of Lipids in CRAC Channel Function

CRAC and SK Channels: Their Molecular Mechanisms Associated with Cancer Cell Development

A bioinformatics analysis: ZFHX4 is associated with metastasis and poor survival in ovarian cancer

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