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Ouabain-induced perturbations in intracellular ionic homeostasis regulate death receptor-mediated apoptosis

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Abstract

Apoptosis is defined by specific morphological and biochemical characteristics including cell shrinkage (termed apoptotic volume decrease), a process that results from the regulation of ion channels and plasma membrane transporter activity. The Na+–K+-ATPase is the predominant pump that controls cell volume and plasma membrane potential in cells and alterations in its function have been suggested to be associated with apoptosis. We report here that the Na+–K+-ATPase inhibitor ouabain, potentiates apoptosis in the human lymphoma Jurkat cells exposed to Fas ligand (FasL) or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) but not other apoptotic agents such as H2O2, thapsigargin or UV-C implicating a role for the Na+–K+-ATPase in death receptor-induced apoptosis. Interestingly, ouabain also potentiated perturbations in cell Ca2+ homeostasis only in conjunction with the apoptotic inducer FasL but not TRAIL. Ouabain did not affect alterations in the intracellular Ca2+ levels in response to H2O2, thapsigargin or UV-C. FasL-induced alterations in Ca2+ were not abolished in Ca2+-free medium but incubation of cells with BAPTA-AM inhibited both Ca2+ perturbations and the ouabain-induced potentiation of FasL-induced apoptosis. Our data suggest that the impairment of the Na+–K+-ATPase activity during apoptosis is linked to perturbations in cell Ca2+ homeostasis that modulate apoptosis induced by the activation of Fas by FasL.

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Acknowledgements

We acknowledge Dr. Elizabeth Murphy and Dr. Gary St. J. Bird for the internal review and comments on this manuscript. We appreciate MS. Maria Sifre, for technical support in the flow cytometry studies. The research was supported by the Intramural Research Program of the NIH/ NIEHS.

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Author notes

  1. Mihalis I. Panayiotidis

    Present address: Department of Pathology, Medical School, University of Ioannina, University Campus, 45110, Ioannina, Greece

  2. Rodrigo Franco

    Present address: Redox Biology Center. School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, 114 VBS 0905, Fair St. & East Campus Loop, Lincoln, NE, 68583, USA

Authors and Affiliations

  1. Laboratory of Signal Transduction, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), MD: F3-07, 111 TW Alexander Drive, P.O. Box 12233, Research Triangle Park, NC, 27709, USA

    Mihalis I. Panayiotidis, Rodrigo Franco, Carl D. Bortner & John A. Cidlowski

Authors
  1. Mihalis I. Panayiotidis
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  2. Rodrigo Franco
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  3. Carl D. Bortner
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  4. John A. Cidlowski
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Corresponding author

Correspondence to John A. Cidlowski.

Additional information

Mihalis I. Panayiotidis and Rodrigo Franco contributed equally to this manuscript.

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Panayiotidis, M.I., Franco, R., Bortner, C.D. et al. Ouabain-induced perturbations in intracellular ionic homeostasis regulate death receptor-mediated apoptosis. Apoptosis 15, 834–849 (2010). https://doi.org/10.1007/s10495-010-0494-8

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