Prostate cancer (PCa) is the second leading cause of cancer-related deaths in men in Western countries, and there is still an urgent need for a better understanding of PCa progression to inspire new treatment strategies. Skp2 is a substrate-recruiting component of the E3 ubiquitin ligase complex, whose activity is regulated through neddylation. Slug is a transcriptional repressor involved in the epithelial-to-mesenchymal transition, which may contribute to therapy resistance. Although Skp2 has previously been associated with a mesenchymal phenotype and prostate cancer progression, the relationship with Slug deserves further elucidation. We have previously shown that a high Gleason score (≥8) is associated with higher Skp2 and lower E-cadherin expression. In this study, significantly increased expression of Skp2, AR, and Slug, along with E-cadherin downregulation, was observed in primary prostate cancer in patients who already had lymph node metastases. Skp2 was slightly correlated with Slug and AR in the whole cohort (Rs 0.32 and 0.37, respectively), which was enhanced for both proteins in patients with high Gleason scores (Rs 0.56 and 0.53, respectively) and, in the case of Slug, also in patients with metastasis to lymph nodes (Rs 0.56). Coexpression of Skp2 and Slug was confirmed in prostate cancer tissues by multiplex immunohistochemistry and confocal microscopy. The same relationship between these two proteins was observed in three sets of prostate epithelial cell lines (PC3, DU145, and E2) and their mesenchymal counterparts. Chemical inhibition of Skp2, but not RNA interference, modestly decreased Slug protein in PC3 and its docetaxel-resistant subline PC3 DR12. Importantly, chemical inhibition of Skp2 by MLN4924 upregulated p27 and decreased Slug expression in PC3, PC3 DR12, and LAPC4 cells. Novel treatment strategies targeting Skp2 and Slug by the neddylation blockade may be promising in advanced prostate cancer, as recently documented for other aggressive solid tumors.

• Klíčová slova
• Skp2 (S-phase kinase-associated protein 2), Slug, immunohistochemistry, multiplex, neddylation, prostate cancer,
• MeSH
• androgenní receptory genetika   metabolismus   MeSH
• antitumorózní látky farmakologie   MeSH
• buňky PC-3 MeSH
• CD antigeny genetika   metabolismus   MeSH
• cyklopentany farmakologie   MeSH
• docetaxel farmakologie   MeSH
• epitelo-mezenchymální tranzice genetika   MeSH
• inhibitor p27 cyklin-dependentní kinasy genetika   metabolismus   MeSH
• kadheriny genetika   metabolismus   MeSH
• lidé MeSH
• lymfatické metastázy MeSH
• malá interferující RNA genetika   metabolismus   MeSH
• nádorové buněčné linie MeSH
• nádory prostaty genetika   metabolismus   patologie   MeSH
• posttranslační úpravy proteinů * MeSH
• prostata metabolismus   patologie   MeSH
• protein NEDD8 genetika   metabolismus   MeSH
• proteiny asociované s kinázou S-fáze antagonisté a inhibitory   genetika   metabolismus   MeSH
• pyrimidiny farmakologie   MeSH
• regulace genové exprese u nádorů MeSH
• rodina transkripčních faktorů Snail genetika   metabolismus   MeSH
• stupeň nádoru MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• androgenní receptory MeSH
• antitumorózní látky MeSH
• CD antigeny MeSH
• CDH1 protein, human MeSH Prohlížeč
• cyklopentany MeSH
• docetaxel MeSH
• inhibitor p27 cyklin-dependentní kinasy MeSH
• kadheriny MeSH
• malá interferující RNA MeSH
• NEDD8 protein, human MeSH Prohlížeč
• pevonedistat MeSH Prohlížeč
• protein NEDD8 MeSH
• proteiny asociované s kinázou S-fáze MeSH
• pyrimidiny MeSH
• rodina transkripčních faktorů Snail MeSH
• SKP2 protein, human MeSH Prohlížeč
• SNAI1 protein, human MeSH Prohlížeč

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.

• MeSH
• androgenní receptory metabolismus   MeSH
• antagonisté androgenů farmakologie   MeSH
• beta-galaktosidasa metabolismus   MeSH
• down regulace účinky léků   MeSH
• fosfohydroláza PTEN metabolismus   MeSH
• IGFBP-3 metabolismus   MeSH
• kathepsin B metabolismus   MeSH
• konfokální mikroskopie MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádory prostaty genetika   metabolismus   patologie   MeSH
• proteiny asociované s kinázou S-fáze genetika   metabolismus   MeSH
• průtoková cytometrie MeSH
• RNA interference MeSH
• signální transdukce účinky léků   MeSH
• stárnutí buněk účinky léků   MeSH
• vimentin metabolismus   MeSH
• western blotting MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• androgenní receptory MeSH
• antagonisté androgenů MeSH
• AR protein, human MeSH Prohlížeč
• beta-galaktosidasa MeSH
• fosfohydroláza PTEN MeSH
• IGFBP-3 MeSH
• kathepsin B MeSH
• proteiny asociované s kinázou S-fáze MeSH
• vimentin MeSH