Na,K-ATPase Isozymes in Colorectal Cancer and Liver Metastases

Bechmann, Marc Baker; Rotoli, Deborah; Morales, Manuel; Maeso, María del Carmen; García, Maria del Pino; Ávila, Julio; Mobasheri, Ali; Martín‐Vasallo, Pablo

doi:10.3389/fphys.2016.00009

Cited by 39 publications

(43 citation statements)

References 67 publications

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“…Each isoform of Na + /K + -ATPase consists of three subunits: one alpha, one beta, and one gamma; of which there are four, three and one kind, respectively (Baker Bechmann et al, 2016;Diederich et al, 2017;Katz et al, 2015). While the alpha subunit of Na + /K + -ATPase is the most well-known cellular target of cardiac glycosides, their selectivity for the various isoforms of Na + /K + -ATPase varies due to the structural diversity of the alpha and beta subunits (Habeck et al, 2016;Katz et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

The cardenolide ouabain suppresses coronaviral replication via augmenting a Na+/K+-ATPase-dependent PI3K_PDK1 axis signaling

Yang

Chang

Lee

et al. 2018

Toxicology and Applied Pharmacology

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Cardenolides are plant-derived toxic substances. Their cytotoxicity and the underlying mechanistic signaling axes have been extensively documented, but only a few anti-viral activities of cardenolides and the associated signaling pathways have been reported. Previously, we reported that a variety of cardenolides impart anti-transmissible gastroenteritis coronavirus (TGEV) activity in swine testicular (ST) cells, through targeting of the cell membrane sodium/potassium pump, Na/K-ATPase. Herein, we further explore the potential signaling cascades associated with this anti-TGEV activity in ST cells. Ouabain, a representative cardenolide, was found to potently diminish TGEV titers and inhibit the TGEV-induced production of IL-6 in a dose dependent manner, with 50% inhibitory concentrations of 37 nM and 23 nM respectively. By pharmacological inhibition and gene silencing, we demonstrated that PI3K_PDK1_RSK2 signaling was induced in TGEV-infected ST cells, and ouabain imparted a degree of anti-TGEV activity via further augmentation of this existing PI3K_PDK1 axis signaling, in a manner dependent upon its association with the Na/K-ATPase. Finally, inhibition of PI3K by LY294002 or PDK1 by BX795 antagonized the anti-viral activity of ouabain and restored the TGEV virus titer and yields. This finding is the first report of a PI3K_PDK1 signaling axis further induced by ouabain and implicated in the suppression of TGEV activity and replication; greatly illuminates the underlying mechanism of cardenolide toxicity; and is expected to result in one or more anti-viral applications for the cardenolides in the future.

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Section: Introductionmentioning

confidence: 99%

The cardenolide ouabain suppresses coronaviral replication via augmenting a Na+/K+-ATPase-dependent PI3K_PDK1 axis signaling

Yang

Chang

Lee

et al. 2018

Toxicology and Applied Pharmacology

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“…5). Moreover, cardenolides inhibit Na + /K + -ATPase with selectivity over the combination of its α (α1-α4) and β (β1-β3) isoforms (Baker Bechmann et al, 2016;Habeck et al, 2016;Katz et al, 2015) and cells express different relative levels of α subunit which also determines their responsiveness to cardenolides (Yang et al, 2009). Thus, the combination of Na + /K + -ATPase α and β isoforms and the specific cell receptor for each coronavirus are suggested to be important for their selectivity of cardenolides against TGEV over MHV.…”

Section: Conclusion and Discussionmentioning

confidence: 99%

“…The combination of Na + /K + -ATPase α and β isoforms determine the selectivity of Na + /K + -ATPase inhibition by cardenolides (Baker Bechmann et al, 2016;Habeck et al, 2016;Katz et al, 2015) and host cell receptors differ in coronaviral specific recognition and infection (Millet et al, 2016;Weiss and Navas-Martin, 2005). We then further tested whether cardenolides exert anti-MHV activity.…”

Section: Cardenolides Do Not Exert Anti-mhv Activitymentioning

confidence: 99%

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Identification of anti-viral activity of the cardenolides, Na + /K + -ATPase inhibitors, against porcine transmissible gastroenteritis virus

Yang

Chang

Hsu

et al. 2017

Toxicology and Applied Pharmacology

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A series of naturally occurring cardenolides that exhibit potent anti-transmissible gastroenteritis virus (TGEV) activity in swine testicular (ST) cells has been identified. In an immunofluorescence assay, these cardenolides were found to diminish the expressions of TGEV nucleocapsid and spike protein, which was used as an indication for viral replication; block TGEV infection induced apoptosis and cytopathic effects; and impart the same trend of inhibitory activity against Na/K-ATPase as for anti-TGEV activity. The viral titer inhibition was found to take place in a dose-dependent manner. Knocking down expression of Na/K-ATPase, the cellular receptor of cardenolides, in ST cells was found to significantly impair the susceptibility of ST cells to TGEV infectivity. Thus, we have identified Na/K-ATPase as an anti-viral drug target and its antagonists, cardenolides, a novel class of anti- TGEV agents.

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“…; Baker Bechmann et al. ), so it is not possible to extrapolate from them to the uterus. The Na + , K + ATPase current has been directly measured in smooth muscle cells from mesenteric artery (Nakamura et al.…”

Section: Discussionmentioning

confidence: 99%

Gestation changes sodium pump isoform expression, leading to changes in ouabain sensitivity, contractility, and intracellular calcium in rat uterus

2017

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Developmental and tissue‐specific differences in isoforms allow Na+, K+‐ATPase function to be tightly regulated, as they control sensitivity to ions and inhibitors. Uterine contraction relies on the activity of the Na+, K+ ATPase, which creates ionic gradients that drive excitation‐contraction coupling. It is unknown whether Na+, K+ ATPase isoforms are regulated throughout pregnancy or whether they have a direct role in modulating uterine contractility. We hypothesized that gestation‐dependent differential expression of isoforms would affect contractile responses to Na+, K+ ATPase α subunit inhibition with ouabain. Our aims were therefore: (1) to determine the gestation‐dependent expression of mRNA transcripts, protein abundance and tissue distribution of Na+, K+ ATPase isoforms in myometrium; (2) to investigate the functional effects of differential isoform expression via ouabain sensitivity; and (3) if changes in contractile responses can be explained by changes in intracellular [Ca2+]. Changes in abundance and distribution of the Na+, K+ ATPase α, β and FXYD1 and 2 isoforms, were studied in rat uterus from nonpregnant, and early, mid‐, and term gestation. All α, β subunit isoforms (1,2,3) and FXYD1 were detected but FXYD2 was absent. The α1 and β1 isoforms were unchanged throughout pregnancy, whereas α2 and α3 significant decreased at term while β2 and FXYD1 significantly increased from mid‐term onwards. These changes in expression correlated with increased functional sensitivity to ouabain, and parallel changes in intracellular Ca2+, measured with Indo‐1. In conclusion, gestation induces specific regulatory changes in expression of Na+, K+ ATPase isoforms in the uterus which influence contractility and may be related to the physiological requirements for successful pregnancy and delivery.

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Na,K-ATPase Isozymes in Colorectal Cancer and Liver Metastases

Cited by 39 publications

References 67 publications

The cardenolide ouabain suppresses coronaviral replication via augmenting a Na+/K+-ATPase-dependent PI3K_PDK1 axis signaling

The cardenolide ouabain suppresses coronaviral replication via augmenting a Na+/K+-ATPase-dependent PI3K_PDK1 axis signaling

Identification of anti-viral activity of the cardenolides, Na + /K + -ATPase inhibitors, against porcine transmissible gastroenteritis virus

Gestation changes sodium pump isoform expression, leading to changes in ouabain sensitivity, contractility, and intracellular calcium in rat uterus

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