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General Sensitization of Melanoma Cells for TRAIL-Induced Apoptosis by the Potassium Channel Inhibitor TRAM-34 Depends on Release of SMAC

The death ligand TRAIL represents a promising therapeutic strategy for metastatic melanoma, however prevalent and inducible resistance limit its applicability. A new approach is presented here for sensitization to TRAIL. It is based on inhibition of the membrane potassium channel KCa3.1 (IK1), which...

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Autores principales: Quast, Sandra-Annika, Berger, Anja, Buttstädt, Nicole, Friebel, Kristin, Schönherr, Roland, Eberle, Jürgen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3377761/
https://www.ncbi.nlm.nih.gov/pubmed/22723988
http://dx.doi.org/10.1371/journal.pone.0039290
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author Quast, Sandra-Annika
Berger, Anja
Buttstädt, Nicole
Friebel, Kristin
Schönherr, Roland
Eberle, Jürgen
author_facet Quast, Sandra-Annika
Berger, Anja
Buttstädt, Nicole
Friebel, Kristin
Schönherr, Roland
Eberle, Jürgen
author_sort Quast, Sandra-Annika
collection PubMed
description The death ligand TRAIL represents a promising therapeutic strategy for metastatic melanoma, however prevalent and inducible resistance limit its applicability. A new approach is presented here for sensitization to TRAIL. It is based on inhibition of the membrane potassium channel KCa3.1 (IK1), which serves fundamental cellular functions related to membrane potential. The selective inhibitor TRAM-34 did not induce apoptosis by itself but synergistically enhanced TRAIL sensitivity and overrode TRAIL resistance in a large panel of melanoma cell lines. Expression of IK1 was also found in mitochondria, and its inhibition resulted in mitochondrial membrane hyperpolarization and an early activation of Bax. The combination of TRAM-34 and TRAIL resulted in massive release of mitochondrial factors, cytochrome c, AIF and SMAC/DIABLO. Bax knockdown and Bcl-2 overexpression abolished apoptosis. Overexpression of XIAP diminished apoptosis by two-fold, and SMAC knockdown almost completely abolished apoptosis. These data uncover the existence of a rheostat in melanoma cells, consisting of inhibitor of apoptosis proteins and SMAC, which regulates TRAIL sensitivity. Thus, a new strategy is described based on mitochondrial membrane channels, which correspond to Bax activation. As both TRAIL and IK1 inhibitors had shown only minor side effects in clinical trials, a clinical application of this combination is conceivable.
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spelling pubmed-33777612012-06-21 General Sensitization of Melanoma Cells for TRAIL-Induced Apoptosis by the Potassium Channel Inhibitor TRAM-34 Depends on Release of SMAC Quast, Sandra-Annika Berger, Anja Buttstädt, Nicole Friebel, Kristin Schönherr, Roland Eberle, Jürgen PLoS One Research Article The death ligand TRAIL represents a promising therapeutic strategy for metastatic melanoma, however prevalent and inducible resistance limit its applicability. A new approach is presented here for sensitization to TRAIL. It is based on inhibition of the membrane potassium channel KCa3.1 (IK1), which serves fundamental cellular functions related to membrane potential. The selective inhibitor TRAM-34 did not induce apoptosis by itself but synergistically enhanced TRAIL sensitivity and overrode TRAIL resistance in a large panel of melanoma cell lines. Expression of IK1 was also found in mitochondria, and its inhibition resulted in mitochondrial membrane hyperpolarization and an early activation of Bax. The combination of TRAM-34 and TRAIL resulted in massive release of mitochondrial factors, cytochrome c, AIF and SMAC/DIABLO. Bax knockdown and Bcl-2 overexpression abolished apoptosis. Overexpression of XIAP diminished apoptosis by two-fold, and SMAC knockdown almost completely abolished apoptosis. These data uncover the existence of a rheostat in melanoma cells, consisting of inhibitor of apoptosis proteins and SMAC, which regulates TRAIL sensitivity. Thus, a new strategy is described based on mitochondrial membrane channels, which correspond to Bax activation. As both TRAIL and IK1 inhibitors had shown only minor side effects in clinical trials, a clinical application of this combination is conceivable. Public Library of Science 2012-06-18 /pmc/articles/PMC3377761/ /pubmed/22723988 http://dx.doi.org/10.1371/journal.pone.0039290 Text en Quast 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
Quast, Sandra-Annika
Berger, Anja
Buttstädt, Nicole
Friebel, Kristin
Schönherr, Roland
Eberle, Jürgen
General Sensitization of Melanoma Cells for TRAIL-Induced Apoptosis by the Potassium Channel Inhibitor TRAM-34 Depends on Release of SMAC
title General Sensitization of Melanoma Cells for TRAIL-Induced Apoptosis by the Potassium Channel Inhibitor TRAM-34 Depends on Release of SMAC
title_full General Sensitization of Melanoma Cells for TRAIL-Induced Apoptosis by the Potassium Channel Inhibitor TRAM-34 Depends on Release of SMAC
title_fullStr General Sensitization of Melanoma Cells for TRAIL-Induced Apoptosis by the Potassium Channel Inhibitor TRAM-34 Depends on Release of SMAC
title_full_unstemmed General Sensitization of Melanoma Cells for TRAIL-Induced Apoptosis by the Potassium Channel Inhibitor TRAM-34 Depends on Release of SMAC
title_short General Sensitization of Melanoma Cells for TRAIL-Induced Apoptosis by the Potassium Channel Inhibitor TRAM-34 Depends on Release of SMAC
title_sort general sensitization of melanoma cells for trail-induced apoptosis by the potassium channel inhibitor tram-34 depends on release of smac
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3377761/
https://www.ncbi.nlm.nih.gov/pubmed/22723988
http://dx.doi.org/10.1371/journal.pone.0039290
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