HERG K+ channel-dependent apoptosis and cell cycle arrest in human glioblastoma cells.

Glioblastoma (GB) is associated with poor patient survival owing to uncontrolled tumor proliferation and resistance to apoptosis. Human ether-a-go-go-related gene K(+) channels (hERG; Kv11.1, KCNH2) are expressed in multiple cancer cells including GB and control cell proliferation and death. We hypo...

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Autores principales:	Ingo Staudacher, Julian Jehle, Kathrin Staudacher, Hans-Werner Pledl, Dieter Lemke, Patrick A Schweizer, Rüdiger Becker, Hugo A Katus, Dierk Thomas
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a8629f74b84f412e92a180c256be423a
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spelling	oai:doaj.org-article:a8629f74b84f412e92a180c256be423a2021-11-18T08:33:25ZHERG K+ channel-dependent apoptosis and cell cycle arrest in human glioblastoma cells.1932-620310.1371/journal.pone.0088164https://doaj.org/article/a8629f74b84f412e92a180c256be423a2014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24516604/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Glioblastoma (GB) is associated with poor patient survival owing to uncontrolled tumor proliferation and resistance to apoptosis. Human ether-a-go-go-related gene K(+) channels (hERG; Kv11.1, KCNH2) are expressed in multiple cancer cells including GB and control cell proliferation and death. We hypothesized that pharmacological targeting of hERG protein would inhibit tumor growth by inducing apoptosis of GB cells. The small molecule hERG ligand doxazosin induced concentration-dependent apoptosis of human LNT-229 (EC50 = 35 µM) and U87MG (EC50 = 29 µM) GB cells, accompanied by cell cycle arrest in the G0/G1 phase. Apoptosis was associated with 64% reduction of hERG protein. HERG suppression via siRNA-mediated knock down mimicked pro-apoptotic effects of doxazosin. Antagonism of doxazosin binding by the non-apoptotic hERG ligand terazosin resulted in rescue of protein expression and in increased survival of GB cells. At the molecular level doxazosin-dependent apoptosis was characterized by activation of pro-apoptotic factors (phospho-erythropoietin-producing human hepatocellular carcinoma receptor tyrosine kinase A2, phospho-p38 mitogen-activated protein kinase, growth arrest and DNA damage inducible gene 153, cleaved caspases 9, 7, and 3), and by inactivation of anti-apoptotic poly-ADP-ribose-polymerase, respectively. In summary, this work identifies doxazosin as small molecule compound that promotes apoptosis and exerts anti-proliferative effects in human GB cells. Suppression of hERG protein is a crucial molecular event in GB cell apoptosis. Doxazosin and future derivatives are proposed as novel options for more effective GB treatment.Ingo StaudacherJulian JehleKathrin StaudacherHans-Werner PledlDieter LemkePatrick A SchweizerRüdiger BeckerHugo A KatusDierk ThomasPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 2, p e88164 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ingo Staudacher Julian Jehle Kathrin Staudacher Hans-Werner Pledl Dieter Lemke Patrick A Schweizer Rüdiger Becker Hugo A Katus Dierk Thomas HERG K+ channel-dependent apoptosis and cell cycle arrest in human glioblastoma cells.
description	Glioblastoma (GB) is associated with poor patient survival owing to uncontrolled tumor proliferation and resistance to apoptosis. Human ether-a-go-go-related gene K(+) channels (hERG; Kv11.1, KCNH2) are expressed in multiple cancer cells including GB and control cell proliferation and death. We hypothesized that pharmacological targeting of hERG protein would inhibit tumor growth by inducing apoptosis of GB cells. The small molecule hERG ligand doxazosin induced concentration-dependent apoptosis of human LNT-229 (EC50 = 35 µM) and U87MG (EC50 = 29 µM) GB cells, accompanied by cell cycle arrest in the G0/G1 phase. Apoptosis was associated with 64% reduction of hERG protein. HERG suppression via siRNA-mediated knock down mimicked pro-apoptotic effects of doxazosin. Antagonism of doxazosin binding by the non-apoptotic hERG ligand terazosin resulted in rescue of protein expression and in increased survival of GB cells. At the molecular level doxazosin-dependent apoptosis was characterized by activation of pro-apoptotic factors (phospho-erythropoietin-producing human hepatocellular carcinoma receptor tyrosine kinase A2, phospho-p38 mitogen-activated protein kinase, growth arrest and DNA damage inducible gene 153, cleaved caspases 9, 7, and 3), and by inactivation of anti-apoptotic poly-ADP-ribose-polymerase, respectively. In summary, this work identifies doxazosin as small molecule compound that promotes apoptosis and exerts anti-proliferative effects in human GB cells. Suppression of hERG protein is a crucial molecular event in GB cell apoptosis. Doxazosin and future derivatives are proposed as novel options for more effective GB treatment.
format	article
author	Ingo Staudacher Julian Jehle Kathrin Staudacher Hans-Werner Pledl Dieter Lemke Patrick A Schweizer Rüdiger Becker Hugo A Katus Dierk Thomas
author_facet	Ingo Staudacher Julian Jehle Kathrin Staudacher Hans-Werner Pledl Dieter Lemke Patrick A Schweizer Rüdiger Becker Hugo A Katus Dierk Thomas
author_sort	Ingo Staudacher
title	HERG K+ channel-dependent apoptosis and cell cycle arrest in human glioblastoma cells.
title_short	HERG K+ channel-dependent apoptosis and cell cycle arrest in human glioblastoma cells.
title_full	HERG K+ channel-dependent apoptosis and cell cycle arrest in human glioblastoma cells.
title_fullStr	HERG K+ channel-dependent apoptosis and cell cycle arrest in human glioblastoma cells.
title_full_unstemmed	HERG K+ channel-dependent apoptosis and cell cycle arrest in human glioblastoma cells.
title_sort	herg k+ channel-dependent apoptosis and cell cycle arrest in human glioblastoma cells.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/a8629f74b84f412e92a180c256be423a
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_version_	1718421640378843136

HERG K+ channel-dependent apoptosis and cell cycle arrest in human glioblastoma cells.

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