NDLI: Herg K+ Channel-Dependent Apoptosis and Cell Cycle Arrest in Human Glioblastoma Cells

Content Provider	PubMed Central
Author	Staudacher, Ingo Jehle, Julian Staudacher, Kathrin Pledl, Hans-werner Lemke, Dieter Schweizer, Patrick A. Becker, Rüdiger Katus, Hugo A. Thomas, Dierk
Editor	Bishopric, Nanette H.
Copyright Year	2014
Abstract	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.
Related Links	http://dx.doi.org/10.1371/journal.pone.0088164
Starting Page	88164
File Format	PDF
ISSN	19326203
e-ISSN	19326203
Journal	PLoS ONE
Issue Number	2
Volume Number	9
Language	English
Publisher	Public Library of Science
Publisher Date	2014-02-01
Access Restriction	Open
Rights Holder	Public Library of Science
Subject Keyword	Biochemistry, Genetics and Molecular Biology(all) Agricultural and Biological Sciences(all) Medicine(all) Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
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4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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