Androgen Depletion Induces Senescence in Prostate Cancer Cells through Down-regulation of Skp2

Although the induction of senescence in cancer cells is a potent mechanism of tumor suppression, senescent cells remain metabolically active and may secrete a broad spectrum of factors that promote tumorigenicity in neighboring malignant cells. Here we show that androgen deprivation therapy (ADT),...

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Main Authors: Zuzana Pernicová, Eva Slabáková, Gvantsa Kharaishvili, Jan Bouchal, Milan Král, Zuzana Kunická, Miroslav Machala, Alois Kozubík, Karel Součcek
Format: Article
Language:English
Published: Elsevier 2011-06-01
Series:Neoplasia: An International Journal for Oncology Research
Online Access:http://www.sciencedirect.com/science/article/pii/S1476558611800448
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spelling doaj-95315d1ad9da43b48a4b6e251a65d3ae2020-11-24T22:55:06ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80022011-06-0113652653610.1593/neo.11182Androgen Depletion Induces Senescence in Prostate Cancer Cells through Down-regulation of Skp2Zuzana Pernicová0Eva Slabáková1Gvantsa Kharaishvili2Jan Bouchal3Milan Král4Zuzana Kunická5Miroslav Machala6Alois Kozubík7Karel Součcek8Department of Cytokinetics, Institute of Biophysics, AS CR, Brno, Czech RepublicDepartment of Cytokinetics, Institute of Biophysics, AS CR, Brno, Czech RepublicLaboratory of Molecular Pathology and Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech RepublicLaboratory of Molecular Pathology and Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech RepublicDepartment of Urology, University Hospital, Olomouc, Czech RepublicDepartment of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech RepublicDepartment of Chemistry and Toxicology, Veterinary Research Institute, Brno, Czech RepublicDepartment of Cytokinetics, Institute of Biophysics, AS CR, Brno, Czech RepublicDepartment of Cytokinetics, Institute of Biophysics, AS CR, Brno, Czech Republic Although the induction of senescence in cancer cells is a potent mechanism of tumor suppression, senescent cells remain metabolically active and may secrete a broad spectrum of factors that promote tumorigenicity in neighboring malignant cells. Here we show that androgen deprivation therapy (ADT), a widely used treatment for advanced prostate cancer, induces a senescence-associated secretory phenotype in prostate cancer epithelial cells, indicated by increases in senescence-associated β-galactosidase activity, heterochromatin protein 1β foci, and expression of cathepsin B and insulin-like growth factor binding protein 3. Interestingly, ADT also induced high levels of vimentin expression in prostate cancer cell lines in vitro and in human prostate tumors in vivo. The induction of the senescence-associated secretory phenotype by androgen depletion was mediated, at least in part, by down-regulation of S-phase kinase-associated protein 2, whereas the neuroendocrine differentiation of prostate cancer cells was under separate control. These data demonstrate a previously unrecognized link between inhibition of androgen receptor signaling, down-regulation of S-phase kinase-associated protein 2, and the appearance of secretory, tumor-promoting senescent cells in prostate tumors. We propose that ADT may contribute to the development of androgen-independent prostate cancer through modulation of the tissue microenvironment by senescent cells. http://www.sciencedirect.com/science/article/pii/S1476558611800448
collection DOAJ
language English
format Article
sources DOAJ
author Zuzana Pernicová
Eva Slabáková
Gvantsa Kharaishvili
Jan Bouchal
Milan Král
Zuzana Kunická
Miroslav Machala
Alois Kozubík
Karel Součcek
spellingShingle Zuzana Pernicová
Eva Slabáková
Gvantsa Kharaishvili
Jan Bouchal
Milan Král
Zuzana Kunická
Miroslav Machala
Alois Kozubík
Karel Součcek
Androgen Depletion Induces Senescence in Prostate Cancer Cells through Down-regulation of Skp2
Neoplasia: An International Journal for Oncology Research
author_facet Zuzana Pernicová
Eva Slabáková
Gvantsa Kharaishvili
Jan Bouchal
Milan Král
Zuzana Kunická
Miroslav Machala
Alois Kozubík
Karel Součcek
author_sort Zuzana Pernicová
title Androgen Depletion Induces Senescence in Prostate Cancer Cells through Down-regulation of Skp2
title_short Androgen Depletion Induces Senescence in Prostate Cancer Cells through Down-regulation of Skp2
title_full Androgen Depletion Induces Senescence in Prostate Cancer Cells through Down-regulation of Skp2
title_fullStr Androgen Depletion Induces Senescence in Prostate Cancer Cells through Down-regulation of Skp2
title_full_unstemmed Androgen Depletion Induces Senescence in Prostate Cancer Cells through Down-regulation of Skp2
title_sort androgen depletion induces senescence in prostate cancer cells through down-regulation of skp2
publisher Elsevier
series Neoplasia: An International Journal for Oncology Research
issn 1476-5586
1522-8002
publishDate 2011-06-01
description Although the induction of senescence in cancer cells is a potent mechanism of tumor suppression, senescent cells remain metabolically active and may secrete a broad spectrum of factors that promote tumorigenicity in neighboring malignant cells. Here we show that androgen deprivation therapy (ADT), a widely used treatment for advanced prostate cancer, induces a senescence-associated secretory phenotype in prostate cancer epithelial cells, indicated by increases in senescence-associated β-galactosidase activity, heterochromatin protein 1β foci, and expression of cathepsin B and insulin-like growth factor binding protein 3. Interestingly, ADT also induced high levels of vimentin expression in prostate cancer cell lines in vitro and in human prostate tumors in vivo. The induction of the senescence-associated secretory phenotype by androgen depletion was mediated, at least in part, by down-regulation of S-phase kinase-associated protein 2, whereas the neuroendocrine differentiation of prostate cancer cells was under separate control. These data demonstrate a previously unrecognized link between inhibition of androgen receptor signaling, down-regulation of S-phase kinase-associated protein 2, and the appearance of secretory, tumor-promoting senescent cells in prostate tumors. We propose that ADT may contribute to the development of androgen-independent prostate cancer through modulation of the tissue microenvironment by senescent cells.
url http://www.sciencedirect.com/science/article/pii/S1476558611800448
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