Sodium-Calcium Exchanger 1 Regulates Epithelial Cell Migration via Calcium-dependent Extracellular Signal-regulated Kinase Signaling

Balasubramaniam, Sona Lakshme; Gopalakrishnapillai, Anilkumar; Gangadharan, Vimal; Duncan, Randall L.; Barwe, Sonali P.

doi:10.1074/jbc.m114.629519

Cited by 18 publications

(15 citation statements)

References 66 publications

(70 reference statements)

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“…Growing evidence supports the contribution of altered Ca 2+ signaling to tumor progression and metastasis, suggesting that agents targeting calcium influx and calcium influx-driven downstream signaling may hopefully offer alternative approaches for cancer therapy [17,18]. Several calcium channels blockers have been investigated in clinical trials [19–21]; however, their efficacy has not been satisfactory for unclear reasons.…”

Section: Discussionmentioning

confidence: 99%

SKF-96365 activates cytoprotective autophagy to delay apoptosis in colorectal cancer cells through inhibition of the calcium/CaMKIIγ/AKT-mediated pathway

et al. 2016

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Store-operated Ca2+ entry (SOCE) inhibitors are emerging as an attractive new generation of anti-cancer drugs. Here, we report that SKF-96365, an SOCE inhibitor, exhibits potent anti-neoplastic activity by inducing cell-cycle arrest and apoptosis in colorectal cancer cells. In the meantime, SKF-96365 also induces cytoprotective autophagy to delay apoptosis by preventing the release of cytochrome c (cyt c) from the mitochondria into the cytoplasm. Mechanistically, SKF-96365 treatment inhibited the calcium/calmodulin-dependent protein kinase IIγ (CaMKIIγ)/AKT signaling cascade in vitro and in vivo. Overexpression of CaMKIIγ or AKT abolished the effects of SKF-96365 on cancer cells, suggesting a critical role of the CaMKIIγ/AKT signaling pathway in SFK-96365-induced biological effects. Moreover, Hydroxychloroquine (HCQ), an FDA-approved drug used to inhibit autophagy, could significantly augment the anti-cancer effect of SFK-96365 in a mouse xenograft model. To our best knowledge, this is the first report to demonstrate that calcium/CaMKIIγ/AKT signaling can regulate apoptosis and autophagy simultaneously in cancer cells, and the combination of the SOCE inhibitor SKF-96365 with autophagy inhibitors represents a promising strategy for treating patients with colorectal cancer.

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Section: Discussionmentioning

confidence: 99%

SKF-96365 activates cytoprotective autophagy to delay apoptosis in colorectal cancer cells through inhibition of the calcium/CaMKIIγ/AKT-mediated pathway

et al. 2016

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“…An interesting cooperation between the Na + /K + -ATPase and the Na + /Ca 2+ -exchanger in cell migration has been unveiled [98]. Stoichiometric efflux of 1 Ca 2+ ion in exchange for the uptake of 3 Na + ions is driven by the high Na + concentration in the extracellular medium and the membrane potential (negative inside) generated by the Na + /K + -ATPase.…”

Section: Calmodulin and Cell Migrationmentioning

confidence: 99%

“…Binding of the regulatory β-subunit of the ATPase to the Na + /Ca 2+ -exchanger inhibits its activity, which increases the [Ca 2+ ] cyt that in turn induces cell migration. This is due to the Ca 2+ /CaM-mediated activation of PI 3 K that activates the mitogen-activated protein kinase (MAPK) pathway resulting in the phosphorylation of myosin light-chain via myosin light-chain kinase (MLCK) and Rho-kinase (ROCK) [98] (see Figure 2).…”

Section: Calmodulin and Cell Migrationmentioning

confidence: 99%

The Role of Calmodulin in Tumor Cell Migration, Invasiveness, and Metastasis

Villalobo

Berchtold

2020

IJMS

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Calmodulin (CaM) is the principal Ca2+ sensor protein in all eukaryotic cells, that upon binding to target proteins transduces signals encoded by global or subcellular-specific changes of Ca2+ concentration within the cell. The Ca2+/CaM complex as well as Ca2+-free CaM modulate the activity of a vast number of enzymes, channels, signaling, adaptor and structural proteins, and hence the functionality of implicated signaling pathways, which control multiple cellular functions. A basic and important cellular function controlled by CaM in various ways is cell motility. Here we discuss the role of CaM-dependent systems involved in cell migration, tumor cell invasiveness, and metastasis development. Emphasis is given to phosphorylation/dephosphorylation events catalyzed by myosin light-chain kinase, CaM-dependent kinase-II, as well as other CaM-dependent kinases, and the CaM-dependent phosphatase calcineurin. In addition, the role of the CaM-regulated small GTPases Rac1 and Cdc42 (cell division cycle protein 42) as well as CaM-binding adaptor/scaffold proteins such as Grb7 (growth factor receptor bound protein 7), IQGAP (IQ motif containing GTPase activating protein) and AKAP12 (A kinase anchoring protein 12) will be reviewed. CaM-regulated mechanisms in cancer cells responsible for their greater migratory capacity compared to non-malignant cells, invasion of adjacent normal tissues and their systemic dissemination will be discussed, including closely linked processes such as the epithelial–mesenchymal transition and the activation of metalloproteases. This review covers as well the role of CaM in establishing metastatic foci in distant organs. Finally, the use of CaM antagonists and other blocking techniques to downregulate CaM-dependent systems aimed at preventing cancer cell invasiveness and metastasis development will be outlined.

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“…We showed earlier that inhibition of NCX1 increases cell migration in kidney epithelial cells (13). Because enhanced migration is one of the characteristics acquired by carcinoma cells, we tested whether NCX1 expression is altered in renal cancers.…”

Section: Expression Of Ncx1 Mrna and Protein Is Down-regulated In Renmentioning

confidence: 98%

“…We showed earlier that functional inhibition of NCX1 led to enhanced cell migration in renal epithelial cells and that NCX1 interacts with adhesion protein, the ␤-subunit of Na,K-ATPase (13). Another study indicated that NCX1 was up-regulated during stroma-induced cell adhesion in the prostate epithelium (14).…”

mentioning

confidence: 95%

Knockdown of sodium–calcium exchanger 1 induces epithelial-to-mesenchymal transition in kidney epithelial cells

Balasubramaniam

Gopalakrishnapillai

Petrelli

et al. 2017

Journal of Biological Chemistry

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Mesenchymal-to-epithelial transition (MET) and epithelial-to-mesenchymal transition (EMT) are important processes in kidney development. Failure to undergo MET during development leads to the initiation of Wilms tumor, whereas EMT contributes to the development of renal cell carcinomas (RCC). The role of calcium regulators in governing these processes is becoming evident. We demonstrated earlier that Na/Ca exchanger 1 (NCX1), a major calcium exporter in renal epithelial cells, regulates epithelial cell motility. Here, we show for the first time that NCX1 mRNA and protein expression was down-regulated in Wilms tumor and RCC. Knockdown of NCX1 in Madin-Darby canine kidney cells induced fibroblastic morphology, increased intercellular junctional distance, and induced paracellular permeability, loss of apico-basal polarity in 3D cultures, and anchorage-independent growth, accompanied by expression of mesenchymal markers. We also provide evidence that NCX1 interacts with and anchors E-cadherin to the cell surface independent of NCX1 ion transport activity. Consistent with destabilization of E-cadherin, NCX1 knockdown cells showed an increase in β-catenin nuclear localization, enhanced transcriptional activity, and up-regulation of downstream targets of the β-catenin signaling pathway. Taken together, knockdown of NCX1 in Madin-Darby canine kidney cells alters epithelial morphology and characteristics by destabilization of E-cadherin and induction of β-catenin signaling.

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Sodium-Calcium Exchanger 1 Regulates Epithelial Cell Migration via Calcium-dependent Extracellular Signal-regulated Kinase Signaling

Cited by 18 publications

References 66 publications

SKF-96365 activates cytoprotective autophagy to delay apoptosis in colorectal cancer cells through inhibition of the calcium/CaMKIIγ/AKT-mediated pathway

SKF-96365 activates cytoprotective autophagy to delay apoptosis in colorectal cancer cells through inhibition of the calcium/CaMKIIγ/AKT-mediated pathway

The Role of Calmodulin in Tumor Cell Migration, Invasiveness, and Metastasis

Knockdown of sodium–calcium exchanger 1 induces epithelial-to-mesenchymal transition in kidney epithelial cells

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