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The Na(+)/H(+) Exchanger Controls Deoxycholic Acid-Induced Apoptosis by a H(+)-Activated, Na(+)-Dependent Ionic Shift in Esophageal Cells
Apoptosis resistance is a hallmark of cancer cells. Typically, bile acids induce apoptosis. However during gastrointestinal (GI) tumorigenesis the cancer cells develop resistance to bile acid-induced cell death. To understand how bile acids induce apoptosis resistance we first need to identify the m...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3161789/ https://www.ncbi.nlm.nih.gov/pubmed/21887327 http://dx.doi.org/10.1371/journal.pone.0023835 |
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author | Goldman, Aaron Chen, HwuDauRw Khan, Mohammad R. Roesly, Heather Hill, Kimberly A. Shahidullah, Mohammad Mandal, Amritlal Delamere, Nicholas A. Dvorak, Katerina |
author_facet | Goldman, Aaron Chen, HwuDauRw Khan, Mohammad R. Roesly, Heather Hill, Kimberly A. Shahidullah, Mohammad Mandal, Amritlal Delamere, Nicholas A. Dvorak, Katerina |
author_sort | Goldman, Aaron |
collection | PubMed |
description | Apoptosis resistance is a hallmark of cancer cells. Typically, bile acids induce apoptosis. However during gastrointestinal (GI) tumorigenesis the cancer cells develop resistance to bile acid-induced cell death. To understand how bile acids induce apoptosis resistance we first need to identify the molecular pathways that initiate apoptosis in response to bile acid exposure. In this study we examined the mechanism of deoxycholic acid (DCA)-induced apoptosis, specifically the role of Na(+)/H(+) exchanger (NHE) and Na(+) influx in esophageal cells. In vitro studies revealed that the exposure of esophageal cells (JH-EsoAd1, CP-A) to DCA (0.2 mM -0.5 mM) caused lysosomal membrane perturbation and transient cytoplasmic acidification. Fluorescence microscopy in conjunction with atomic absorption spectrophotometry demonstrated that this effect on lysosomes correlated with influx of Na(+), subsequent loss of intracellular K(+), an increase of Ca(2+) and apoptosis. However, ethylisopropyl-amiloride (EIPA), a selective inhibitor of NHE, prevented Na(+), K(+) and Ca(2+) changes and caspase 3/7 activation induced by DCA. Ouabain and amphotericin B, two drugs that increase intracellular Na(+) levels, induced similar changes as DCA (ion imbalance, caspase3/7 activation). On the contrary, DCA-induced cell death was inhibited by medium with low a Na(+) concentrations. In the same experiments, we exposed rat ileum ex-vivo to DCA with or without EIPA. Severe tissue damage and caspase-3 activation was observed after DCA treatment, but EIPA almost fully prevented this response. In summary, NHE-mediated Na(+) influx is a critical step leading to DCA-induced apoptosis. Cells tolerate acidification but evade DCA-induced apoptosis if NHE is inhibited. Our data suggests that suppression of NHE by endogenous or exogenous inhibitors may lead to apoptosis resistance during GI tumorigenesis. |
format | Online Article Text |
id | pubmed-3161789 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-31617892011-09-01 The Na(+)/H(+) Exchanger Controls Deoxycholic Acid-Induced Apoptosis by a H(+)-Activated, Na(+)-Dependent Ionic Shift in Esophageal Cells Goldman, Aaron Chen, HwuDauRw Khan, Mohammad R. Roesly, Heather Hill, Kimberly A. Shahidullah, Mohammad Mandal, Amritlal Delamere, Nicholas A. Dvorak, Katerina PLoS One Research Article Apoptosis resistance is a hallmark of cancer cells. Typically, bile acids induce apoptosis. However during gastrointestinal (GI) tumorigenesis the cancer cells develop resistance to bile acid-induced cell death. To understand how bile acids induce apoptosis resistance we first need to identify the molecular pathways that initiate apoptosis in response to bile acid exposure. In this study we examined the mechanism of deoxycholic acid (DCA)-induced apoptosis, specifically the role of Na(+)/H(+) exchanger (NHE) and Na(+) influx in esophageal cells. In vitro studies revealed that the exposure of esophageal cells (JH-EsoAd1, CP-A) to DCA (0.2 mM -0.5 mM) caused lysosomal membrane perturbation and transient cytoplasmic acidification. Fluorescence microscopy in conjunction with atomic absorption spectrophotometry demonstrated that this effect on lysosomes correlated with influx of Na(+), subsequent loss of intracellular K(+), an increase of Ca(2+) and apoptosis. However, ethylisopropyl-amiloride (EIPA), a selective inhibitor of NHE, prevented Na(+), K(+) and Ca(2+) changes and caspase 3/7 activation induced by DCA. Ouabain and amphotericin B, two drugs that increase intracellular Na(+) levels, induced similar changes as DCA (ion imbalance, caspase3/7 activation). On the contrary, DCA-induced cell death was inhibited by medium with low a Na(+) concentrations. In the same experiments, we exposed rat ileum ex-vivo to DCA with or without EIPA. Severe tissue damage and caspase-3 activation was observed after DCA treatment, but EIPA almost fully prevented this response. In summary, NHE-mediated Na(+) influx is a critical step leading to DCA-induced apoptosis. Cells tolerate acidification but evade DCA-induced apoptosis if NHE is inhibited. Our data suggests that suppression of NHE by endogenous or exogenous inhibitors may lead to apoptosis resistance during GI tumorigenesis. Public Library of Science 2011-08-22 /pmc/articles/PMC3161789/ /pubmed/21887327 http://dx.doi.org/10.1371/journal.pone.0023835 Text en Goldman et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Goldman, Aaron Chen, HwuDauRw Khan, Mohammad R. Roesly, Heather Hill, Kimberly A. Shahidullah, Mohammad Mandal, Amritlal Delamere, Nicholas A. Dvorak, Katerina The Na(+)/H(+) Exchanger Controls Deoxycholic Acid-Induced Apoptosis by a H(+)-Activated, Na(+)-Dependent Ionic Shift in Esophageal Cells |
title | The Na(+)/H(+) Exchanger Controls Deoxycholic Acid-Induced Apoptosis by a H(+)-Activated, Na(+)-Dependent Ionic Shift in Esophageal Cells |
title_full | The Na(+)/H(+) Exchanger Controls Deoxycholic Acid-Induced Apoptosis by a H(+)-Activated, Na(+)-Dependent Ionic Shift in Esophageal Cells |
title_fullStr | The Na(+)/H(+) Exchanger Controls Deoxycholic Acid-Induced Apoptosis by a H(+)-Activated, Na(+)-Dependent Ionic Shift in Esophageal Cells |
title_full_unstemmed | The Na(+)/H(+) Exchanger Controls Deoxycholic Acid-Induced Apoptosis by a H(+)-Activated, Na(+)-Dependent Ionic Shift in Esophageal Cells |
title_short | The Na(+)/H(+) Exchanger Controls Deoxycholic Acid-Induced Apoptosis by a H(+)-Activated, Na(+)-Dependent Ionic Shift in Esophageal Cells |
title_sort | na(+)/h(+) exchanger controls deoxycholic acid-induced apoptosis by a h(+)-activated, na(+)-dependent ionic shift in esophageal cells |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3161789/ https://www.ncbi.nlm.nih.gov/pubmed/21887327 http://dx.doi.org/10.1371/journal.pone.0023835 |
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