Cardiotonic Steroids Differentially Affect Intracellular Na+ and [Na+] /[K+] -independent Signaling in C7-MDCK Cells

Akimova, Olga A.; Bagrov, Alexei Y.; Лопина, О.Д.; Kamernitsky, A. V.; Tremblay, Johanne; Hamet, Pavel; Orlov, Sergei N.

doi:10.1074/jbc.m411011200

Cited by 69 publications

(73 citation statements)

References 32 publications

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“…Our observation that ouabain stimulates cell growth is in line with findings from several other laboratories that showed that ouabain stimulates growth of smooth muscle cells and renal epithelial cells from both rodent and human species (11)(12)(13)38,39). These effects have been attributed to the activation of several intracellular signaling pathways, among them activation of Ras/MAPK-ERK kinase/mitogen-activated protein kinase cascade (3,4).…”

Section: Discussionsupporting

confidence: 91%

Low Doses of Ouabain Protect from Serum Deprivation–Triggered Apoptosis and Stimulate Kidney Cell Proliferation via Activation of NF-κB

Li¹,

Zelenin²,

Aperia³

et al. 2006

Journal of the American Society of Nephrology

124

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It now generally is agreed that Na,K-ATPase, in addition to its role in the maintenance of Na ؉ and K ؉ gradients across the cell membrane, plays a role in communicating information from the extracellular environment to intracellular signaling pathways. It was reported recently that interaction between ouabain-bound Na,K-ATPase and the 1,4,5-trisphosphate receptor (IP 3 R) triggers slow calcium oscillations and activation of NF-B. Here it is demonstrated that this signaling pathway can serve to prevent cell death and promote cell growth. Rat renal proximal tubular cells in primary culture first were grown in the presence of 10% serum and then exposed to 0.2% serum for 24 h to induce apoptosis. Serum starvation increased the apoptotic index from 1.21 ؎ 0.26 to 14.01 ؎ 1.17%. Ouabain in concentrations that did not inhibit Na,K-ATPase activity (1 to 10 nM) completely abolished the apoptotic effect of serum starvation. Ouabain protection from apoptosis was not observed when release of calcium from intracellular stores via the IP 3 R was prevented. It was shown that the NH 2 terminal tail of the Na,K-ATPase ␣ subunit plays a key role in ouabain-triggered calcium oscillations. It was found that ouabain did not protect from apoptosis in serum-deprived cells that expressed a mutant Na,K-ATPase ␣ subunit with deletion of the NH 2 terminal tail. . Recent studies suggest that Na,K-ATPase, in addition to being the major determinant of intracellular ion composition, may act as a signal transducer (2-5).Ouabain, a steroid derivative, is a specific ligand of Na,KATPase that dose-dependently inhibits the activity of Na,KATPase (6). Noninhibitory doses of ouabain activate the signaling function of Na,K-ATPase. The signaling cascade that is triggered by Na,K-ATPase is complex, and several different pathways have been implicated (7-9). We recently reported that ouabain can trigger an interaction between Na,K-ATPase and the inositol 1,4,5-trisphosphate (IP 3 ) receptor, which results in low-frequency Ca 2ϩ oscillations and activation of the transcription factor NF-B. This phenomenon was observed in rat renal proximal tubular cells in primary culture and in a kidney cell line (10).A number of recent studies have demonstrated that ouabain in noninhibitory doses can promote cell proliferation (11-13). Because NF-B has an antiapoptotic effect (14), we speculated that ouabain also might act to protect from apoptosis. Here we demonstrate that noninhibitory doses of ouabain can protect rat renal proximal tubular cells from serum deprivation-triggered apoptosis, albeit not from pharmacologically staurosporinetriggered apoptosis. We show that protection from serum-triggered apoptosis depends on NF-B activation. Normal kidney development is critically dependent on a well-controlled balance between cell proliferation and apoptosis (15). Accumulating evidence suggests that ouabain is a mammalian hormone, produced in the adrenal glands and the hypothalamus (16,17). Therefore, ouabain might play an important role as a modulator of kidney growth ...

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Section: Discussionsupporting

confidence: 91%

Low Doses of Ouabain Protect from Serum Deprivation–Triggered Apoptosis and Stimulate Kidney Cell Proliferation via Activation of NF-κB

Li¹,

Zelenin²,

Aperia³

et al. 2006

Journal of the American Society of Nephrology

124

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“…The authors did not report whether MDCK cells in these experiments underwent EMT (12,37). Another study showed that a concentration of 1 M ouabain was toxic for MDCK cells (1).…”

Section: Discussionmentioning

confidence: 92%

The cardiotonic steroid hormone marinobufagenin induces renal fibrosis: implication of epithelial-to-mesenchymal transition

Fedorova¹,

Raju²,

El-Okdi³

et al. 2009

American Journal of Physiology-Renal Physiology

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“…29) Both Ca 2ϩ influx and K ϩ efflux have been proposed to mediate cardiac glycosides cytotoxicity. 13,30) We hypothesized that the caspase-independent cell death might be associated with the cardiac glycosides induced Ca 2ϩ increase. Previous study reports that digoxin-induced toxicity of prostate cancer cells is accompanied by the increase of intracellular Ca 2ϩ , 14,31) which is believed to be a key factor in apoptosis.…”

Section: Resultsmentioning

confidence: 99%

Antiproliferative Activity of Derivatives of Ouabain, Digoxin and Proscillaridin A in Human MCF-7 and MDA-MB-231 Breast Cancer Cells

Winnicka

Bielawski

Bielawska

et al. 2008

Biological & Pharmaceutical Bulletin

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Three derivatives of ouabain, digoxin and proscillaridin A containing the carboxylic group instead of the lactone moiety were synthesized and examined for cytotoxicity in human breast cancer cells. Evaluation of the cytotoxicity of these compounds employing an MTT assay and inhibition of [ 3 H]thymidine incorporation into DNA in both MCF-7 and MDA-MB-231 breast cancer cells demonstrated that compound 3, the most active of the series, proved to be only slightly less potent than proscillaridin A. We evaluated the effects of these compounds 1-3 on change in intracellular Ca 2؉ , appearance of apoptosis, inhibition of DNA topoisomerase I and II, and the activity of caspase-3 in breast cancer cells. These studies indicate that the increase in potency for 3 may be related, in part, to an activation of caspase-3, increasing free calcium concentration and topoisomerase II inhibition. All these data emphasize the potential usefulness of these derivatives of cardiac glycosides as anticancer agents.Key words cardiac glycoside; cytotoxicity; breast cancer cell; DNA topoisomerase Biol. Pharm. Bull. 31(6) 1131-1140 (2008) © 2008 Pharmaceutical Society of Japan * To whom correspondence should be addressed. e-mail: kwin@amb.edu.pl mine, penicillin and streptomycin were obtained from Quality Biologicals (U.S.A.). [ 3 H]Thymidine (6.7 Ci/mmol) was purchased from NEN (U.S.A.), and Scintillation Coctail "Ultima Gold XR" from Packard (U.S.A.). Nitrocellulose membrane (0.2 mm), sodium dodecylsulfate (SDS), polyacrylamide and molecular weight standards were received from Bio-Rad Laboratories (U.S.A.). Topoisomerase I and II, supercoiled pHOT1 DNA, supercoiled pRYG DNA, etoposide, camptothecin were purchased from TopoGEN (U.S.A.).Chemistry The structures of all the compounds were confirmed by ). Melting points were determined on Büchi 535 melting-point (Germany) apparatus and were uncorrected. Elemental analysis of C, H, was performed on a Perkin Elmer 240 analyser (U.S.A.) and satisfactory results within Ϯ0.4% of calculated values were obtained. Chemical shifts are expressed in d value (ppm). Multiplicity of resonance peaks are indicated as singlet (s), doublet (d), triplet (t), quarter (q), and multiplet (m).(Z)-4-Hydroxy-3-((1R,3S,5S,8R,9S,10R,11R,13R,14S, 17R)-1,5,11,14-tetrahydroxy-10-(hydroxymethyl)-13-methyl-3-((2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yloxy)hexadecahydro-1H-cyclopenta-[a]phenanthren-17-yl)but-2-enoic Acid (Compound 1) Ouabain (0.57 g, 0.78 mmol) was suspended in a mixture of 2 ml of THF and 2 ml of 1 M LiOH. The reaction was allowed to stir at room temperature until no starting ouabain could be detected by TLC (CHCl 3 : MeOH 5 : 1). The basic mixture was acidified to pH 4 with 2 M HCl and diluted with acetone. The precipated acid was filtred and dried in vacuo at room temperature to afford 0. 17.11, 17.62, 22.96, 26.07, 32.30, 33.20, 34.91, 35.37, 38.94, 46.58, 47.37, 48.28, 48.76, 49.45, 62.57, 63.61, 66.70, 68.17, 69.22, 70.56, 70.68, 72.18, 73.54, 83.30, 97.08, 115.96, 172.3...

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Cardiotonic Steroids Differentially Affect Intracellular Na+ and [Na+] /[K+] -independent Signaling in C7-MDCK Cells

Cited by 69 publications

References 32 publications

Low Doses of Ouabain Protect from Serum Deprivation–Triggered Apoptosis and Stimulate Kidney Cell Proliferation via Activation of NF-κB

Low Doses of Ouabain Protect from Serum Deprivation–Triggered Apoptosis and Stimulate Kidney Cell Proliferation via Activation of NF-κB

The cardiotonic steroid hormone marinobufagenin induces renal fibrosis: implication of epithelial-to-mesenchymal transition

Antiproliferative Activity of Derivatives of Ouabain, Digoxin and Proscillaridin A in Human MCF-7 and MDA-MB-231 Breast Cancer Cells

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