2011
Pernicová, Zuzana; Slabáková, Eva; Kharaishvili, Gvantsa; Bouchal, Jan; Král, Milan; Kunická, Zuzana; Machala, Miroslav; Kozubík, Alois; Souček, Karel
Androgen depletion induces senescence in prostate cancer cells through down-regulation of Skp2. Journal Article
In: Neoplasia (New York, N.Y.), vol. 13, no. 6, pp. 526–536, 2011, ISSN: 1476-5586 1522-8002, (Place: United States).
Abstract | Links | BibTeX | Tags: Androgen Antagonists/*pharmacology, Androgen/metabolism, beta-Galactosidase/metabolism, Blotting, Cathepsin B/metabolism, Cell Line, Cellular Senescence/*drug effects, Confocal, Down-Regulation/*drug effects, Flow Cytometry, Humans, Insulin-Like Growth Factor Binding Protein 3/metabolism, Male, Microscopy, Prostatic Neoplasms/genetics/metabolism/pathology, PTEN Phosphohydrolase/metabolism, Receptors, RNA Interference, S-Phase Kinase-Associated Proteins/genetics/*metabolism, Signal Transduction/drug effects, Tumor, Vimentin/metabolism, Western
@article{pernicova_androgen_2011,
title = {Androgen depletion induces senescence in prostate cancer cells through down-regulation of Skp2.},
author = {Zuzana Pernicová and Eva Slabáková and Gvantsa Kharaishvili and Jan Bouchal and Milan Král and Zuzana Kunická and Miroslav Machala and Alois Kozubík and Karel Souček},
doi = {10.1593/neo.11182},
issn = {1476-5586 1522-8002},
year = {2011},
date = {2011-06-01},
journal = {Neoplasia (New York, N.Y.)},
volume = {13},
number = {6},
pages = {526–536},
abstract = {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.},
note = {Place: United States},
keywords = {Androgen Antagonists/*pharmacology, Androgen/metabolism, beta-Galactosidase/metabolism, Blotting, Cathepsin B/metabolism, Cell Line, Cellular Senescence/*drug effects, Confocal, Down-Regulation/*drug effects, Flow Cytometry, Humans, Insulin-Like Growth Factor Binding Protein 3/metabolism, Male, Microscopy, Prostatic Neoplasms/genetics/metabolism/pathology, PTEN Phosphohydrolase/metabolism, Receptors, RNA Interference, S-Phase Kinase-Associated Proteins/genetics/*metabolism, Signal Transduction/drug effects, Tumor, Vimentin/metabolism, Western},
pubstate = {published},
tppubtype = {article}
}
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.
Blanárová, Olga Vondálová; Jelínková, Iva; Szöor, Arpád; Skender, Belma; Soucek, Karel; Horváth, Viktor; Vaculová, Alena; Andera, Ladislav; Sova, Petr; Szöllosi, János; Hofmanová, Jirina; Vereb, György; Kozubík, Alois
In: Carcinogenesis, vol. 32, no. 1, pp. 42–51, 2011, ISSN: 1460-2180 0143-3334, (Place: England).
Abstract | Links | BibTeX | Tags: Amantadine/*analogs & derivatives/pharmacology, Apoptosis/*drug effects/physiology, Blotting, Cell Line, Cell Separation, Cisplatin/*pharmacology, Confocal, Flow Cytometry, Fluorescent Antibody Technique, Humans, Microscopy, Neoplasms/*metabolism, Organoplatinum Compounds/*pharmacology, Protein Transport/drug effects, Receptors, Reverse Transcriptase Polymerase Chain Reaction, RNA Interference, Signal Transduction/*drug effects/physiology, TNF-Related Apoptosis-Inducing Ligand/*metabolism, TNF-Related Apoptosis-Inducing Ligand/metabolism, Tumor, Western
@article{vondalova_blanarova_cisplatin_2011,
title = {Cisplatin and a potent platinum(IV) complex-mediated enhancement of TRAIL-induced cancer cells killing is associated with modulation of upstream events in the extrinsic apoptotic pathway.},
author = {Olga Vondálová Blanárová and Iva Jelínková and Arpád Szöor and Belma Skender and Karel Soucek and Viktor Horváth and Alena Vaculová and Ladislav Andera and Petr Sova and János Szöllosi and Jirina Hofmanová and György Vereb and Alois Kozubík},
doi = {10.1093/carcin/bgq220},
issn = {1460-2180 0143-3334},
year = {2011},
date = {2011-01-01},
journal = {Carcinogenesis},
volume = {32},
number = {1},
pages = {42–51},
abstract = {TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) can selectively trigger apoptosis in various cancer cell types. However, many cancer cells are resistant to death receptor-mediated apoptosis. Combination therapy with platinum complexes may affect TRAIL-induced signaling via modulation of various steps in apoptotic pathways. Here, we show that cisplatin or a more potent platinum(IV) complex LA-12 used in 20-fold lower concentration enhanced killing effects of TRAIL in human colon and prostate cancer cell lines via stimulation of caspase activity and overall apoptosis. Both platinum complexes increased DR5 surface expression in colon cancer cells. Small interfering RNA-mediated DR5 silencing rescued cells from sensitizing effects of platinum drugs on TRAIL-induced caspase-8 activation and apoptosis, showing the functional importance of DR5 in the effects observed. In addition, both cisplatin and LA-12 triggered the relocalization of DR4 and DR5 receptors to lipid rafts and accelerated internalization of TRAIL, which may also affect TRAIL signaling. Collectively, modulations of the initial steps of the extrinsic apoptotic pathway at the level of DR5 and plasma membrane are important for sensitization of colon and prostate cancer cells to TRAIL-induced apoptosis mediated by LA-12 and cisplatin.},
note = {Place: England},
keywords = {Amantadine/*analogs & derivatives/pharmacology, Apoptosis/*drug effects/physiology, Blotting, Cell Line, Cell Separation, Cisplatin/*pharmacology, Confocal, Flow Cytometry, Fluorescent Antibody Technique, Humans, Microscopy, Neoplasms/*metabolism, Organoplatinum Compounds/*pharmacology, Protein Transport/drug effects, Receptors, Reverse Transcriptase Polymerase Chain Reaction, RNA Interference, Signal Transduction/*drug effects/physiology, TNF-Related Apoptosis-Inducing Ligand/*metabolism, TNF-Related Apoptosis-Inducing Ligand/metabolism, Tumor, Western},
pubstate = {published},
tppubtype = {article}
}
TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) can selectively trigger apoptosis in various cancer cell types. However, many cancer cells are resistant to death receptor-mediated apoptosis. Combination therapy with platinum complexes may affect TRAIL-induced signaling via modulation of various steps in apoptotic pathways. Here, we show that cisplatin or a more potent platinum(IV) complex LA-12 used in 20-fold lower concentration enhanced killing effects of TRAIL in human colon and prostate cancer cell lines via stimulation of caspase activity and overall apoptosis. Both platinum complexes increased DR5 surface expression in colon cancer cells. Small interfering RNA-mediated DR5 silencing rescued cells from sensitizing effects of platinum drugs on TRAIL-induced caspase-8 activation and apoptosis, showing the functional importance of DR5 in the effects observed. In addition, both cisplatin and LA-12 triggered the relocalization of DR4 and DR5 receptors to lipid rafts and accelerated internalization of TRAIL, which may also affect TRAIL signaling. Collectively, modulations of the initial steps of the extrinsic apoptotic pathway at the level of DR5 and plasma membrane are important for sensitization of colon and prostate cancer cells to TRAIL-induced apoptosis mediated by LA-12 and cisplatin.