Ouabain activates signaling pathways associated with cell death in human neuroblastoma

Куликов, А. В.; Eva, Alexander; Kirch, Ulrike; Boldyrev, Alexander A.; Scheiner‐Bobis, Georgios

doi:10.1016/j.bbamem.2007.04.012

Cited by 103 publications

(73 citation statements)

References 64 publications

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“…*P Ͻ 0.05 vs. 10 ng/ml TRAIL-treated cells. (11,15). Consistently, we found ROS induction in response to ouabain treatment in H292 lung cancer cells, while TRAIL treatment caused only an insignificant effect on cellular ROS level.…”

Section: Ouabain Sensitizes H460 Human Lung Cancer Cells To Trailindusupporting

confidence: 84%

Ouabain downregulates Mcl-1 and sensitizes lung cancer cells to TRAIL-induced apoptosis

Chanvorachote

Pongrakhananon

2013

American Journal of Physiology-Cell Physiology

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Section: Ouabain Sensitizes H460 Human Lung Cancer Cells To Trailindusupporting

confidence: 84%

Ouabain downregulates Mcl-1 and sensitizes lung cancer cells to TRAIL-induced apoptosis

Chanvorachote

Pongrakhananon

2013

American Journal of Physiology-Cell Physiology

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“…In smooth muscle, HeLa, and neuroblastoma cells, ouabain induces apoptosis (22,23). In contrast, ouabain has an antiapoptotic effect in LLC-PK1 and kidney cells (24), preventing apoptosis induced through serum deprivation in renal proximal tubular rat cells (24).…”

Section: Resultsmentioning

confidence: 99%

Ouabain modulates epithelial cell tight junction

Larre

Lázaro

Contreras

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

102

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Epithelial cells treated with high concentrations of ouabain (e.g., 1 μM) retrieve molecules involved in cell contacts from the plasma membrane and detach from one another and their substrates. On the basis of this observation, we suggested that ouabain might also modulate cell contacts at low, nontoxic levels (10 or 50 nM). To test this possibility, we analyzed its effect on a particular type of cell-cell contact: the tight junction (TJ). We demonstrate that at concentrations that neither inhibit K + pumping nor disturb the K + balance of the cell, ouabain modulates the degree of sealing of the TJ as measured by transepithelial electrical resistance (TER) and the flux of neutral 3 kDa dextran (J DEX ). This modulation is accompanied by changes in the levels and distribution patterns of claudins 1, 2, and 4. Interestingly, changes in TER, J DEX , and claudins behavior are mediated through signal pathways containing ERK1/2 and c-Src, which have distinct effects on each physiological parameter and claudin type. These observations support the theory that at low concentrations, ouabain acts as a modulator of cell-cell contacts.claudins | c-Src | ERK1/2 | Madin-Darby canine kidney | occludin S everal lines of evidence, including the high affinity and specificity of ouabain for Na + ,K + -ATPase, suggest that endogenous ouabain analogs might exist. In keeping with this possibility, Hamlyn et al.(1) demonstrated the presence of a substance in plasma that cannot be distinguished from ouabain even by specific antibodies and mass spectrometry (1-4). Endogenous ouabain levels are increased during exercise (5) and in pathological conditions such as arterial hypertension (6-9) and eclampsia (10), raising the possibility that ouabain functions as a hormone and prompting efforts to elucidate physiological role.We have previously demonstrated that ouabain acts on cell-substrate and cell-cell contacts in Madin-Darby canine kidney (MDCK) cells. At 1 μM, ouabain binding to the Na + ,K + -ATPase results in pump inhibition and disassembly of molecules from the tight, adherens, and focal junctions (i.e., a P→A mechanism from pump to adhesion) (11). Consistent with these results, Rajasekaran et al. (12) have observed that 0.5 μM ouabain acts on the tight junction (TJ), decreasing transepithelial electrical resistance (TER) and increasing mannitol and inulin permeability in cultures of human retinal pigment epithelial cells. Furthermore, we have shown that in cocultures of wild-type MDCK and ouabain-resistant MDCK cells, ouabain treatment increases the expression of connexin 32, but not 26 or 43, and increases cell-cell communication via gap junctions to rescue the wild-type cells (13). Although these effects indicate that toxic levels of ouabain affect the structure and function of cell-cell junctions, we do not know how lower levels of ouabain affect adhesive structures.In the present work, we focus on this question and demonstrate that 10 nM ouabain affects neither Na + ,K + -ATPase nor the K + balance of the cells and does not indu...

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“…Early epidemiologic studies by Stenkvist et al reported significantly lower mortality rates of cancer patients under cardiac glycoside treatment (25,26). Because then, numerous in vitro studies have reported potent antiproliferative effects of these compounds in a panel of cancer cell lines, including breast (27), prostate (28), melanoma (29), pancreatic (30), lung (31), leukemia (32), neuroblastoma (33), and renal adenocarcinoma (ref. 34; Table 2).…”

Section: Discussionmentioning

confidence: 99%

High-Throughput Screening Identifies Cardiac Glycosides as Potent Inhibitors of Human Tissue Kallikrein Expression: Implications for Cancer Therapies

Prassas

Paliouras

Datti

et al. 2008

Clinical Cancer Research

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Purpose: Human tissue kallikreins (KLK) comprise a subgroup of 15 homologous secreted serine proteases. Primarily known for their clinical use as cancer biomarkers (e.g., PSA), KLKs have recently been directly implicated in cancer-related processes, including invasion, angiogenesis, and tumor growth regulation. Therefore, the identification of compounds that would modulate expression of KLKs might be of considerable therapeutic value. Experimental Design: A cell-based high-throughput screening (HTS) of three small molecule libraries (f4,500 compounds) was undertaken; KLK expression in the breast cancer cell line MDA-MB-468 was assessed with sensitive ELISAs. Results: The initial screening resulted in 66 ''putative hits'' that decreased KLK5 expression by at least 50% over control. Secondary screening and mini-dose-response assays resulted in 21 ''validated hits.'' These 21 compounds were clustered in only three distinct functional families and were further analyzed in vitro to determine their effectiveness (IC 50 s). Hits that failed to show dose-responsiveness or interfered with the viability of the cells were excluded. Multiple members of the cardiac glycoside family were found to be novel inhibitors of KLK expression, acting at low concentrations (10-50 nmol/L). Furthermore, members of the same family induced marked decreases in c-MYC and c-FOS expression, in a dose-dependent manner that correlated the KLK inhibition, suggesting a transcriptional mechanism of regulation of KLK expression. Conclusions: We conclude that cardiac glycosides can dramatically suppress the transcription of KLKs and that these effects may be linked to proto-oncogene (c-myc/fos) expression. These findings may partially explain the recently realized antineoplastic actions of cardiac glycosides.

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Ouabain activates signaling pathways associated with cell death in human neuroblastoma

Cited by 103 publications

References 64 publications

Ouabain downregulates Mcl-1 and sensitizes lung cancer cells to TRAIL-induced apoptosis

Ouabain downregulates Mcl-1 and sensitizes lung cancer cells to TRAIL-induced apoptosis

Ouabain modulates epithelial cell tight junction

High-Throughput Screening Identifies Cardiac Glycosides as Potent Inhibitors of Human Tissue Kallikrein Expression: Implications for Cancer Therapies

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