Resveratrol Specifically Kills Cancer Cells by a Devastating Increase in the Ca<sup>2+</sup> Coupling between the Greatly Tethered Endoplasmic Reticulum and Mitochondria

© 2016 The Author(s) Published by S. Karger AG, Basel. Copyright: All rights reserved. Background/Aims: Resveratrol and its derivate piceatannol are known to induce cancer cell-specific cell death. While multiple mechanisms of actions have been described including the inhibition of ATP synthase, cha...

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Main Authors: Corina T. Madreiter-Sokolowski, Benjamin Gottschalk, Warisara Parichatikanond, Emrah Eroglu, Christiane Klec, Markus Waldeck-Weiermair, Roland Malli, Wolfgang F. Graier
Other Authors: Medizinische Universitat Graz
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Published: 2018
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Online Access:https://repository.li.mahidol.ac.th/handle/123456789/42934
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spelling th-mahidol.429342019-03-14T15:03:59Z Resveratrol Specifically Kills Cancer Cells by a Devastating Increase in the Ca<sup>2+</sup> Coupling between the Greatly Tethered Endoplasmic Reticulum and Mitochondria Corina T. Madreiter-Sokolowski Benjamin Gottschalk Warisara Parichatikanond Emrah Eroglu Christiane Klec Markus Waldeck-Weiermair Roland Malli Wolfgang F. Graier Medizinische Universitat Graz Mahidol University Biochemistry, Genetics and Molecular Biology © 2016 The Author(s) Published by S. Karger AG, Basel. Copyright: All rights reserved. Background/Aims: Resveratrol and its derivate piceatannol are known to induce cancer cell-specific cell death. While multiple mechanisms of actions have been described including the inhibition of ATP synthase, changes in mitochondrial membrane potential and ROS levels, the exact mechanisms of cancer specificity of these polyphenols remain unclear. This paper is designed to reveal the molecular basis of the cancer-specific initiation of cell death by resveratrol and piceatannol. Methods: The two cancer cell lines EA.hy926 and HeLa, and somatic short-term cultured HUVEC were used. Cell viability and caspase 3/7 activity were tested. Mitochondrial, cytosolic and endoplasmic reticulum Ca2+ as well as cytosolic and mitochondrial ATP levels were measured using single cell fluorescence microscopy and respective genetically-encoded sensors. Mitochondria-ER junctions were analyzed applying super-resolution SIM and ImageJ-based image analysis. Results: Resveratrol and piceatannol selectively trigger death in cancer but not somatic cells. Hence, these polyphenols strongly enhanced mitochondrial Ca2+ uptake in cancer exclusively. Resveratrol and piceatannol predominantly affect mitochondrial but not cytosolic ATP content that yields in a reduced SERCA activity. Decreased SERCA activity and the strongly enriched tethering of the ER and mitochondria in cancer cells result in an enhanced MCU/Letm1-dependent mitochondrial Ca2+ uptake upon intracellular Ca2+ release exclusively in cancer cells. Accordingly, resveratrol/piceatannol-induced cancer cell death could be prevented by siRNA-mediated knock-down of MCU and Letm1. Conclusions: Because their greatly enriched ER-mitochondria tethering, cancer cells are highly susceptible for resveratrol/piceatannol-induced reduction of SERCA activity to yield mitochondrial Ca2+ overload and subsequent cancer cell death. 2018-12-11T02:09:17Z 2019-03-14T08:03:59Z 2018-12-11T02:09:17Z 2019-03-14T08:03:59Z 2016-09-01 Article Cellular Physiology and Biochemistry. Vol.39, No.4 (2016), 1404-1420 10.1159/000447844 14219778 10158987 2-s2.0-84988410069 https://repository.li.mahidol.ac.th/handle/123456789/42934 Mahidol University SCOPUS https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84988410069&origin=inward
institution Mahidol University
building Mahidol University Library
continent Asia
country Thailand
Thailand
content_provider Mahidol University Library
collection Mahidol University Institutional Repository
topic Biochemistry, Genetics and Molecular Biology
spellingShingle Biochemistry, Genetics and Molecular Biology
Corina T. Madreiter-Sokolowski
Benjamin Gottschalk
Warisara Parichatikanond
Emrah Eroglu
Christiane Klec
Markus Waldeck-Weiermair
Roland Malli
Wolfgang F. Graier
Resveratrol Specifically Kills Cancer Cells by a Devastating Increase in the Ca<sup>2+</sup> Coupling between the Greatly Tethered Endoplasmic Reticulum and Mitochondria
description © 2016 The Author(s) Published by S. Karger AG, Basel. Copyright: All rights reserved. Background/Aims: Resveratrol and its derivate piceatannol are known to induce cancer cell-specific cell death. While multiple mechanisms of actions have been described including the inhibition of ATP synthase, changes in mitochondrial membrane potential and ROS levels, the exact mechanisms of cancer specificity of these polyphenols remain unclear. This paper is designed to reveal the molecular basis of the cancer-specific initiation of cell death by resveratrol and piceatannol. Methods: The two cancer cell lines EA.hy926 and HeLa, and somatic short-term cultured HUVEC were used. Cell viability and caspase 3/7 activity were tested. Mitochondrial, cytosolic and endoplasmic reticulum Ca2+ as well as cytosolic and mitochondrial ATP levels were measured using single cell fluorescence microscopy and respective genetically-encoded sensors. Mitochondria-ER junctions were analyzed applying super-resolution SIM and ImageJ-based image analysis. Results: Resveratrol and piceatannol selectively trigger death in cancer but not somatic cells. Hence, these polyphenols strongly enhanced mitochondrial Ca2+ uptake in cancer exclusively. Resveratrol and piceatannol predominantly affect mitochondrial but not cytosolic ATP content that yields in a reduced SERCA activity. Decreased SERCA activity and the strongly enriched tethering of the ER and mitochondria in cancer cells result in an enhanced MCU/Letm1-dependent mitochondrial Ca2+ uptake upon intracellular Ca2+ release exclusively in cancer cells. Accordingly, resveratrol/piceatannol-induced cancer cell death could be prevented by siRNA-mediated knock-down of MCU and Letm1. Conclusions: Because their greatly enriched ER-mitochondria tethering, cancer cells are highly susceptible for resveratrol/piceatannol-induced reduction of SERCA activity to yield mitochondrial Ca2+ overload and subsequent cancer cell death.
author2 Medizinische Universitat Graz
author_facet Medizinische Universitat Graz
Corina T. Madreiter-Sokolowski
Benjamin Gottschalk
Warisara Parichatikanond
Emrah Eroglu
Christiane Klec
Markus Waldeck-Weiermair
Roland Malli
Wolfgang F. Graier
format Article
author Corina T. Madreiter-Sokolowski
Benjamin Gottschalk
Warisara Parichatikanond
Emrah Eroglu
Christiane Klec
Markus Waldeck-Weiermair
Roland Malli
Wolfgang F. Graier
author_sort Corina T. Madreiter-Sokolowski
title Resveratrol Specifically Kills Cancer Cells by a Devastating Increase in the Ca<sup>2+</sup> Coupling between the Greatly Tethered Endoplasmic Reticulum and Mitochondria
title_short Resveratrol Specifically Kills Cancer Cells by a Devastating Increase in the Ca<sup>2+</sup> Coupling between the Greatly Tethered Endoplasmic Reticulum and Mitochondria
title_full Resveratrol Specifically Kills Cancer Cells by a Devastating Increase in the Ca<sup>2+</sup> Coupling between the Greatly Tethered Endoplasmic Reticulum and Mitochondria
title_fullStr Resveratrol Specifically Kills Cancer Cells by a Devastating Increase in the Ca<sup>2+</sup> Coupling between the Greatly Tethered Endoplasmic Reticulum and Mitochondria
title_full_unstemmed Resveratrol Specifically Kills Cancer Cells by a Devastating Increase in the Ca<sup>2+</sup> Coupling between the Greatly Tethered Endoplasmic Reticulum and Mitochondria
title_sort resveratrol specifically kills cancer cells by a devastating increase in the ca<sup>2+</sup> coupling between the greatly tethered endoplasmic reticulum and mitochondria
publishDate 2018
url https://repository.li.mahidol.ac.th/handle/123456789/42934
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