The presence of angiotensin type 2 (AT2) receptors in mitochondria and their role in NO generation and cell aging were recently demonstrated in various human and mouse non-tumour cells. We investigated the intracellular distribution of AT2 receptors including their presence in mitochondria and their role in the induction of apoptosis and cell death in cultured human uterine leiomyosarcoma (SK-UT-1) cells and control human uterine smooth muscle cells (HutSMC). The intracellular levels of the AT2 receptor are low in proliferating SK-UT-1 cells but the receptor is substantially up-regulated in quiescent SK-UT-1 cells with high densities in mitochondria. Activation of the cell membrane AT2 receptors by a concomitant treatment with angiotensin II and the AT1 receptor antagonist, losartan, induces apoptosis but does not affect the rate of cell death. We demonstrate for the first time that the high-affinity, non-peptide AT2 receptor agonist, Compound 21 (C21), penetrates the cell membrane of quiescent SK-UT-1 cells, activates intracellular AT2 receptors and induces rapid cell death; approximately 70% of cells died within 24 h. The cells, which escaped cell death, displayed activation of the mitochondrial apoptotic pathway, i.e. down-regulation of the Bcl-2 protein, induction of the Bax protein and activation of caspase-3. All quiescent SK-UT-1 cells died within 5 days after treatment with a single dose of C21. C21 was devoid of cytotoxic effects in proliferating SK-UT-1 cells and in quiescent HutSMC. Our results point to a new, unique approach enabling the elimination non-cycling uterine leiomyosarcoma cells providing that they over-express the AT2 receptor.
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Research Article|
February 11 2015
Activation of intracellular angiotensin AT2 receptors induces rapid cell death in human uterine leiomyosarcoma cells
Yi Zhao;
Yi Zhao
1
*Department of Nuclear Medicine, Molecular Imaging, Diagnostics and Therapy, University Hospitals of Schleswig-Holstein, Campus Kiel, 24105, Kiel, Germany
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Ulf Lützen;
Ulf Lützen
1
*Department of Nuclear Medicine, Molecular Imaging, Diagnostics and Therapy, University Hospitals of Schleswig-Holstein, Campus Kiel, 24105, Kiel, Germany
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Jürgen Fritsch;
Jürgen Fritsch
†Institute of Immunology, University Hospitals of Schleswig-Holstein, Campus Kiel, 24105, Kiel, Germany
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Maaz Zuhayra;
Maaz Zuhayra
*Department of Nuclear Medicine, Molecular Imaging, Diagnostics and Therapy, University Hospitals of Schleswig-Holstein, Campus Kiel, 24105, Kiel, Germany
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Stefan Schütze;
Stefan Schütze
†Institute of Immunology, University Hospitals of Schleswig-Holstein, Campus Kiel, 24105, Kiel, Germany
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Ulrike M. Steckelings;
Ulrike M. Steckelings
‡Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, 5000 Odense, Denmark
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Chiara Recanti;
Chiara Recanti
§Cardiovascular Research Institute Maastricht, 6229 ER Maastricht, The Netherlands
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Pawel Namsoleck;
Pawel Namsoleck
§Cardiovascular Research Institute Maastricht, 6229 ER Maastricht, The Netherlands
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Thomas Unger;
Thomas Unger
§Cardiovascular Research Institute Maastricht, 6229 ER Maastricht, The Netherlands
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Juraj Culman
║Institute of Experimental and Clinical Pharmacology, University Hospitals of Schleswig-Holstein, Campus Kiel, 24105, Kiel, Germany
Correspondence: Dr Juraj Culman (email juraj.culman@pharmakologie.uni-kiel.de).
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Publisher: Portland Press Ltd
Received:
October 02 2014
Revision Received:
December 01 2014
Accepted:
December 09 2014
Accepted Manuscript online:
December 09 2014
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2015 Biochemical Society
2015
Clin Sci (Lond) (2015) 128 (9): 567–578.
Article history
Received:
October 02 2014
Revision Received:
December 01 2014
Accepted:
December 09 2014
Accepted Manuscript online:
December 09 2014
Citation
Yi Zhao, Ulf Lützen, Jürgen Fritsch, Maaz Zuhayra, Stefan Schütze, Ulrike M. Steckelings, Chiara Recanti, Pawel Namsoleck, Thomas Unger, Juraj Culman; Activation of intracellular angiotensin AT2 receptors induces rapid cell death in human uterine leiomyosarcoma cells. Clin Sci (Lond) 1 May 2015; 128 (9): 567–578. doi: https://doi.org/10.1042/CS20140627
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