title: Androgen depletion induces senescence in prostate cancer cells through down-regulation of Skp2.
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.
authors.affiliation: Department of Cytokinetics, Institute of Biophysics, AS CR, Brno, Czech Republic.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Pernicová
authors.forename: Eva
authors.initials: E
authors.lastname: Slabáková
authors.forename: Gvantsa
authors.initials: G
authors.lastname: Kharaishvili
authors.forename: Jan
authors.initials: J
authors.lastname: Bouchal
authors.forename: Milan
authors.initials: M
authors.lastname: Král
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Kunická
authors.forename: Miroslav
authors.initials: M
authors.lastname: Machala
authors.forename: Alois
authors.initials: A
authors.lastname: Kozubík
authors.forename: Karel
authors.initials: K
authors.lastname: Souček
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology*; D015153:Blotting, Western; D002401:Cathepsin B / Q000378:metabolism; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects*; D005434:Flow Cytometry; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism; D008297:Male; D018613:Microscopy, Confocal; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D011944:Receptors, Androgen / Q000378:metabolism; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014746:Vimentin / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D018972:Insulin-Like Growth Factor Binding Protein 3; D011944:Receptors, Androgen; D044786:S-Phase Kinase-Associated Proteins; D014746:Vimentin; D051059:PTEN Phosphohydrolase; D001616:beta-Galactosidase; D002401:Cathepsin B