Crosstalk between Na+,K+-ATPase and a volume-regulated anion channel in membrane microdomains of human cancer cells

Fujii, Takuto; Shimizu, Takahiro; Yamamoto, Shota; Funayama, Keisuke; Fujita, Katsushi; Tabuchi, Yoshiaki; Ikari, Akira; Takeshima, Hiroshi; Sakai, Hideki

doi:10.1016/j.bbadis.2018.09.014

Cited by 39 publications

(27 citation statements)

References 35 publications

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“…Na + /K + -ATPase (NKA) is a multifunctional transmembrane protein that plays a crucial role in cell adhesion ( 14 ), cell movement ( 43 ), cell proliferation and apoptosis ( 8 ), and signal transduction ( 44 ). Emerging studies have shown the abnormal expression ( 6 ) and the prognosis of NKA in various cancers ( 9 ).…”

Section: Discussionmentioning

confidence: 99%

Integrative Transcriptomic, Proteomic and Functional Analysis Reveals ATP1B3 as a Diagnostic and Potential Therapeutic Target in Hepatocellular Carcinoma

Cai

et al. 2021

Front. Immunol.

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The Na+/K+-ATPase (NKA), has been proposed as a signal transducer involving various pathobiological processes, including tumorigenesis. However, the clinical relevance of NKA in hepatocellular carcinoma (HCC) has not been well studied. This study revealed the upregulation of mRNA of ATP1A1, ATP1B1, and ATP1B3 in HCC using TCGA, ICGC, and GEO database. Subsequently, ATP1B3 was demonstrated as an independent prognostic factor of overall survival (OS) of HCC. To investigate the potential mechanisms of ATP1B3 in HCC, we analyzed the co-expression network using LinkedOmics and found that ATP1B3 co-expressed genes were associated with immune-related biological processes. Furthermore, we found that ATP1B3 was correlated immune cell infiltration and immune-related cytokines expression in HCC. The protein level of ATP1B3 was also validated as a prognostic significance and was correlated with immune infiltration in HCC using two proteomics datasets. Finally, functional analysis revealed that ATP1B3 was increased in HCC cells and tissues, silenced ATP1B3 repressed HCC cell proliferation, migration, and promoted HCC cell apoptosis and epithelial to mesenchymal transition (EMT). In conclusion, these findings proved that ATP1B3 could be an oncogene and it was demonstrated as an independent prognostic factor and correlated with immune infiltration in HCC, revealing new insights into the prognostic role and potential immune regulation of ATP1B3 in HCC progression and provide a novel possible therapeutic strategy for HCC.

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Section: Discussionmentioning

confidence: 99%

Integrative Transcriptomic, Proteomic and Functional Analysis Reveals ATP1B3 as a Diagnostic and Potential Therapeutic Target in Hepatocellular Carcinoma

Cai

et al. 2021

Front. Immunol.

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“…The flavonoid Dh-morin suppressed VRAC currents but did not reduce proliferation of HUVEC cells [43], and siRNA against LRRC8A did not affect the proliferation rate in HeLa cells [42]. The DCPIB treatment even inhibited the antiproliferative effect of cardiac glycosides that correlated with an increase in VRAC activity in HT-29 cells [44].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, the flavonoid Dh-morin was shown to effectively inhibit endogenous VRAC currents in endothelial cells, without impairing the proliferation of human umbilical vein endothelial (HUVEC) cells [43], arguing against a crucial role for the VRAC in the cell cycle progression of this cell type. The anti-proliferative effect of submicromolar concentrations of cardiac glycosides was even linked, albeit not necessarily directly, to an increase of VRAC activity in HT-29 colorectal cancer cells and could be blocked by the VRAC inhibitor DCPIB [44].…”

Section: Introductionmentioning

confidence: 99%

The Volume-Regulated Anion Channel LRRC8/VRAC Is Dispensable for Cell Proliferation and Migration

Liu

Stauber

2019

IJMS

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Cells possess the capability to adjust their volume for various physiological processes, presumably including cell proliferation and migration. The volume-regulated anion channel (VRAC), formed by LRRC8 heteromers, is critically involved in regulatory volume decrease of vertebrate cells. The VRAC has also been proposed to play a role in cell cycle progression and cellular motility. Indeed, recent reports corroborated this notion, with potentially important implications for the VRAC in cancer progression. In the present study, we examined the role of VRAC during cell proliferation and migration in several cell types, including C2C12 myoblasts, human colon cancer HCT116 cells, and U251 and U87 glioblastoma cells. Surprisingly, neither pharmacological inhibition of VRAC with 4-[(2-Butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)oxy]butanoic acid (DCPIB), carbenoxolone or 5-nitro-2-(3-phenylpropyl-amino)benzoic acid (NPPB), nor siRNA-mediated knockdown or gene knockout of the essential VRAC subunit LRRC8A affected cell growth and motility in any of the investigated cell lines. Additionally, we found no effect of the VRAC inhibition using siRNA treatment or DCPIB on PI3K/Akt signaling in glioblastoma cells. In summary, our work suggests that VRAC is dispensable for cell proliferation or migration.

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“…Furthermore, the possibility of digoxin’s anticancer effect via PPARα and apoptotic caspase cascade pathways was suggested. Although several studies have suggested that digoxin is a potential candidate anticancer agent 43–45 , no definitive evidence exists yet. Our results provide a framework for uncovering and validating previously overlooked/undetected associations between digoxin use and anticancer effects by using both clinical and bioinformatics databases.…”

Section: Discussionmentioning

confidence: 99%

Integrative analysis of clinical and bioinformatics databases to identify anticancer properties of digoxin

Yokoyama

Sugimoto

Nakagawa

et al. 2019

Sci Rep

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Cardiac glycosides, such as digoxin, inhibit Na+/K+-ATPases and cause secondary activation of Na+/Ca2+ exchangers. Preclinical investigations have suggested that digoxin may have anticancer properties. In order to clarify the functional mechanisms of digoxin in cancer, we performed an integrative analysis of clinical and bioinformatics databases. The US Food and Drug Administration Adverse Event Reporting System and the Japan Medical Data Center claims database were used as clinical databases to evaluate reporting odds ratios and adjusted sequence ratios, respectively. The BaseSpace Correlation Engine and Connectivity Map bioinformatics databases were used to investigate molecular pathways related to digoxin anticancer mechanisms. Clinical database analyses suggested an inverse association between digoxin and four cancers: gastric, colon, prostate and haematological malignancy. The bioinformatics database analysis suggested digoxin may exert an anticancer effect via peroxisome proliferator-activated receptor α and apoptotic caspase cascade pathways. Our integrative analysis revealed the possibility of digoxin as a drug repositioning candidate for cancers.

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Crosstalk between Na+,K+-ATPase and a volume-regulated anion channel in membrane microdomains of human cancer cells

Cited by 39 publications

References 35 publications

Integrative Transcriptomic, Proteomic and Functional Analysis Reveals ATP1B3 as a Diagnostic and Potential Therapeutic Target in Hepatocellular Carcinoma

Integrative Transcriptomic, Proteomic and Functional Analysis Reveals ATP1B3 as a Diagnostic and Potential Therapeutic Target in Hepatocellular Carcinoma

The Volume-Regulated Anion Channel LRRC8/VRAC Is Dispensable for Cell Proliferation and Migration

Integrative analysis of clinical and bioinformatics databases to identify anticancer properties of digoxin

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