Pro- and anti-inflammatory cytokines may influence proliferation, migration, invasion, and other cellular events of prostate cancer (PCa) cells. The hyaluronan receptor CD44, which is regulated by Interleukin (IL)-4, is a prostate basal cell marker. CD44high /CD49bhigh expressing cells have been demonstrated to have tumor-initiating characteristics. Here, we aimed to analyze the effects of long-term IL-4 treatment on CD44/CD49b expression, migration, proliferation, and clonogenic potential of basal-like PCa cells. To this end PC3 cells were treated over 30 passages with 5 ng/mL IL-4 (PC3-IL4) resulting in an increased population of CD44high expressing cells. This was concurrent with a clonal outgrowth of cuboid-shaped cells, with increased size and light absorbance properties. Flow cytometry revealed that the PC3-IL4 CD44high expressing subpopulation corresponds to the CD49bhigh population. Isolation of the PC3-IL4 CD44high /CD49bhigh subpopulation via fluorescence-associated cell sorting showed increased migrative, proliferative, and clonogenic potential compared to the CD44low /CD49blow subpopulation. In conclusion, IL-4 increases a PC3 subpopulation with tumor-initiating characteristics. Thus, IL-4, similar to other cytokines may be a regulator of tumor-initiation and hence, may present a suitable therapy target in combination with current treatment options.

• MeSH
• antigeny CD44 biosyntéza   MeSH
• buňky PC-3 MeSH
• integrin alfa2 biosyntéza   MeSH
• interleukin-4 metabolismus   MeSH
• lidé MeSH
• nádorová transformace buněk metabolismus   patologie   MeSH
• nádorové proteiny metabolismus   MeSH
• nádory prostaty metabolismus   patologie   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

We report results showing that the silencing of carbonic anhydrase I (siCA1) in prostatic (PC3) tumour cells has a significant impact on exosome formation. An increased diameter, concentration and diversity of the produced exosomes were noticed as a consequence of this knock-down. The protein composition of the exosomes' cargo was also altered. Liquid chromatography and mass spectrometry analyses identified 42 proteins significantly altered in PC3 siCA1 exosomes compared with controls. The affected proteins are mainly involved in metabolic processes, biogenesis, cell component organization and defense/immunity. Interestingly, almost all of them have been described as 'enhancers' of tumour development through the promotion of cell proliferation, migration and invasion. Thus, our results indicate that the reduced expression of the CA1 protein enhances the malignant potential of PC3 cells.

• MeSH
• buňky PC-3 MeSH
• energetický metabolismus genetika   MeSH
• exozómy genetika   metabolismus   MeSH
• karboanhydrasa I genetika   metabolismus   MeSH
• lidé MeSH
• nádory prostaty genetika   metabolismus   patologie   MeSH
• pohyb buněk genetika   MeSH
• proliferace buněk genetika   MeSH
• regulace genové exprese enzymů * MeSH
• regulace genové exprese u nádorů * MeSH
• RNA interference * MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Skp2 is a crucial component of SCFSkp2 E3 ubiquitin ligase and is often overexpressed in various types of cancer, including prostate cancer (PCa). The epithelial-to-mesenchymal transition (EMT) is involved in PCa progression. The acquisition of a mesenchymal phenotype that results in a cancer stem cell (CSC) phenotype in PCa was described. Therefore, we aimed to investigate the expression and localization of Skp2 in clinical samples from patients with PCa, the association of Skp2 with EMT status, and the role of Skp2 in prostate CSC. We found that nuclear expression of Skp2 was increased in patients with PCa compared to those with benign hyperplasia, and correlated with high Gleason score in PCa patients. Increased Skp2 expression was observed in PCa cell lines with mesenchymal and CSC-like phenotype compared to their epithelial counterparts. Conversely, the CSC-like phenotype was diminished in cells in which SKP2 expression was silenced. Furthermore, we observed that Skp2 downregulation led to the decrease in subpopulation of CD44+CD24- cancer stem-like cells. Finally, we showed that high expression levels of both CD24 and CD44 were associated with favorable recurrence-free survival for PCa patients. This study uncovered the Skp2-mediated CSC-like phenotype with oncogenic functions in PCa.

• MeSH
• antigen CD24 genetika   MeSH
• antigeny CD44 genetika   MeSH
• buňky PC-3 MeSH
• epitelo-mezenchymální tranzice * MeSH
• lidé MeSH
• myši nahé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádorové kmenové buňky metabolismus   fyziologie   MeSH
• nádory prostaty genetika   metabolismus   patofyziologie   MeSH
• proteiny asociované s kinázou S-fáze genetika   MeSH
• regulace genové exprese u nádorů * MeSH
• stupeň nádoru MeSH
• xenogenní modely - testy protinádorové aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Upregulated Wnt/β-catenin signaling is associated with increased cancer cell resistance and cancer cell-elicited immunosuppression. In non-neoplastic immune cells, upregulated Wnt/β-catenin is, however, associated with either immunosuppression or immunostimulation. Therefore, it is difficult to predict the therapeutic impact inhibitors of Wnt/β-catenin signaling will have when combined with cancer immunotherapy. Here, we evaluated the benefit(s) of the Wnt/β-catenin signaling inhibitor XAV939 in the in vitro elimination of LNCaP prostate cancer cells when cocultured with lymphocytes from patients with localized biochemically recurrent prostate cancer (BRPCa). We found that 5 µM XAV939 inhibited β-catenin translocation to the nucleus in LNCaP cells and CD4+ BRPCa lymphocytes without affecting their proliferation and viability. Preconditioning BRPCa lymphocytes with 5 µM XAV939 accelerated the elimination of LNCaP cells during the coculturing. However, during subsequent re-coculturing with fresh LNCaP cells, BRPCa lymphocytes were no longer able to eliminate LNCaP cells unless coculturing and re-coculturing were performed in the presence of 5 µM XAV939. Comparable results were obtained for PC-3 prostate cancer cells. These findings provide a rationale for combining cell-based immunotherapy of PCa with inhibitors of Wnt/β-catenin signaling.

• MeSH
• beta-katenin antagonisté a inhibitory   metabolismus   MeSH
• buňky PC-3 MeSH
• CD4-pozitivní T-lymfocyty účinky léků   imunologie   MeSH
• heterocyklické sloučeniny tricyklické farmakologie   MeSH
• imunoterapie metody   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádory prostaty farmakoterapie   genetika   patologie   MeSH
• proteiny Wnt antagonisté a inhibitory   metabolismus   MeSH
• protinádorové látky farmakologie   MeSH
• senioři MeSH
• signální dráha Wnt účinky léků   MeSH
• T-lymfocyty cytologie   imunologie   MeSH
• tankyrasy antagonisté a inhibitory   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The identification of fibroblasts and cancer-associated fibroblasts from human cancer tissue using surface markers is difficult, especially because the markers used currently are usually not expressed solely by fibroblasts, and the identification of fibroblast-specific surface molecules is still under investigation. It was aimed to compare three commercially available antibodies in the detection of different surface epitopes of fibroblasts (anti-fibroblast, fibroblast activation protein α, and fibroblast surface protein). The specificity of their expression, employing fibroblast cell lines and tumor-derived fibroblasts from breast and prostate tissues was investigated. Both the established fibroblast cell line HFF-1 and ex vivo primary fibroblasts isolated from breast and prostate cancer tissues expressed the tested surface markers to different degrees. Surprisingly, those markers were expressed also by permanent cell lines of epithelial origin, both benign and cancer-derived (breast-cell lines MCF 10A, HMLE and prostate-cell lines BPH-1, DU 145, and PC-3). The expression of fibroblast activation protein α increased on the surface of previously described models of epithelial cells undergoing epithelial-to-mesenchymal transition in response to treatment with TGF-β1. To prove the co-expression of the fibroblast markers on cells of epithelial origin, we used freshly dissociated human prostate and breast cancer tissues. The results confirmed the co-expression of anti-fibroblast and fibroblast surface protein on CD31/CD45-negative/EpCAM-positive epithelial cells. In summary, our data support the findings that the tested fibroblast markers are not fibroblast specific and may be expressed also by cells of epithelial origin (e.g., cells undergoing EMT). Therefore, the expression of these markers should be interpreted with caution, and the combination of several epitopes for both positive (anti-fibroblast or fibroblast activation protein α) and negative (EpCAM) identification of fibroblasts from breast and prostate tumor tissues is advised. © 2017 International Society for Advancement of Cytometry.

• MeSH
• adhezní molekula epiteliálních buněk metabolismus   MeSH
• antigeny CD31 metabolismus   MeSH
• antigeny CD45 metabolismus   MeSH
• biologické markery metabolismus   MeSH
• buňky PC-3 MeSH
• epitelo-mezenchymální tranzice fyziologie   MeSH
• epitelové buňky metabolismus   MeSH
• fibroblasty metabolismus   MeSH
• lidé MeSH
• membránové proteiny metabolismus   MeSH
• nádorové buněčné linie MeSH
• nádory prostaty metabolismus   MeSH
• nádory prsu metabolismus   MeSH
• serinové endopeptidasy metabolismus   MeSH
• transformující růstový faktor beta1 metabolismus   MeSH
• želatinasy metabolismus   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Nanoparticles are commonly used in diagnostics and therapy. They are also increasingly being implemented in cancer immunotherapy because of their ability to deliver drugs and modulate the immune system. However, the effect of nanoparticles on immune cells involved in the anti-tumor immune response is not well understood. The study reported here showed that nickel-doped maghemite nanoparticles (FN NP) are differentially cytotoxic to cultured mouse and human cancer cell lines, causing their death without negatively impacting the subsequent anticancer immune response. It also found that FN NP induced cell death in the mouse colorectal cancer cell line CT26 and human prostate cancer cell line PC-3, but not in the human prostate cancer cell line LNCaP. The induced cancer cell death did not affect the phenotype and responsivity of the isolated mouse peritoneal macrophages, or ex vivo-generated mouse bone marrow-derived, or human monocyte-derived dendritic cells. Additionally, the induced cancer cell death did not prevent the ex vivo-generated mouse or human dendritic cells from stimulating lymphocytes and enriching cell cultures with cancer cell-reactive T-cells. In conclusion, this study shows that FN NP could be a valuable platform for targeting cancer cells without causing immunosuppressive effects on the subsequent anticancer immune response.

• MeSH
• buňky PC-3 MeSH
• dendritické buňky * imunologie   MeSH
• imunoterapie * metody   MeSH
• lidé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory prostaty imunologie   terapie   MeSH
• nádory imunologie   terapie   MeSH
• nikl * chemie   imunologie   MeSH
• železité sloučeniny chemie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

• Publikační typ
• abstrakt z konference MeSH

Zoledronic Acid (ZA) rapidly concentrates into the bone and reduces skeletal-related events and pain in bone metastatic prostate cancer (PCa), but exerts only a limited or absent impact as anti-cancer activity. Recently, we developed self-assembling nanoparticles (NPS) encapsulating zoledronic acid (NZ) that allowed a higher intratumor delivery of the drug compared with free zoledronic acid (ZA) in in vivo cancer models of PCa. Increasing evidence suggests that Bone Marrow (BM) Mesenchymal stromal cells (BM-MSCs) are recruited into the stroma of developing tumors where they contribute to progression by enhancing tumor growth and metastasis.We demonstrated that treatment with NZ decreased migration and differentiation into adipocytes and osteoblasts of MSCs and inhibited osteoclastogenesis. Treatment with NZ reduced the capability of MSCs to promote the migration and the clonogenic growth of the prostate cancer cell lines PC3 and DU145. The levels of Interleukin-6 and of the pro-angiogenic factors VEGF and FGF-2 were significantly reduced in MSC-CM derived from MSCs treated with NZ, and CCL5 secretion was almost totally abolished. Moreover, treatment of MSCs with supernatants from PC3 cells, leading to tumor-educated MSCs (TE-MSCs), increased the secretion of IL-6, CCL5, VEGF and FGF-2 by MSCs and increased their capability to increase PC3 cells clonogenic growth. Treatment with NZ decreased cytokine secretion and the pro-tumorigenic effects also of TE-MSCS. In conclusion, demonstrating that NZ is capable to inhibit the cross talk between MSCs and PCa, this study provides a novel insight to explain the powerful anticancer activity of NZ on PCa.

• MeSH
• bisfosfonáty aplikace a dávkování   MeSH
• buněčná diferenciace účinky léků   MeSH
• cytokiny metabolismus   MeSH
• imidazoly aplikace a dávkování   MeSH
• látky indukující angiogenezi metabolismus   MeSH
• lidé MeSH
• mezenchymální kmenové buňky cytologie   účinky léků   metabolismus   MeSH
• mezibuněčná komunikace účinky léků   MeSH
• nádorové buněčné linie MeSH
• nádorové mikroprostředí účinky léků   MeSH
• nádory prostaty metabolismus   patologie   MeSH
• nanočástice MeSH
• osteoblasty cytologie   účinky léků   metabolismus   MeSH
• osteoklasty cytologie   účinky léků   metabolismus   MeSH
• pohyb buněk účinky léků   MeSH
• tukové buňky cytologie   účinky léků   metabolismus   MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Drug resistance is a serious problem in cancer therapy. Growing evidence has shown that docosahexaenoic acid has anti-inflammatory and chemopreventive abilities. Studies have shown that autophagy inhibition and ferroptosis are promising therapeutic strategies for overcoming multidrug resistance. This study was aimed to examine whether docosahexaenoic acid (DHA) could reverse docetaxel resistance in prostate cancer cells. Cell survival was examined by MTT and colony formation. Protein expression was determined by Western blot. Reactive oxygen species (ROS) production was measured by flow cytometry. DHA displayed anti-cancer effects on proliferation, colony formation, migration, apoptosis, autophagy and epithelial mesenchymal transition. Glutathione-S-transferase π is an enzyme that plays an important role in drug resistance. DHA inhibited GSTπ protein expression and induced cytoprotective autophagy by regulating the PI3K/AKT signalling pathway in PC3R cells. DHA combined with PI3K inhibitor (LY294002) enhanced apoptosis by alleviating the expression of LC3B, (pro-) caspase- 3 and (uncleaved) PARP. DHA induced ferroptosis by attenuating the expression of glutathione peroxidase 4 (GPX4) and nuclear erythroid 2-related factor 2 (Nrf2). DHA-treated PC3R cells produced ROS. The ROS and cytotoxicity were reversed by treatment with ferrostatin-1. DHA combined with docetaxel inhibited EMT by regulating the expression of E-cadhein and N-cadherin. In summary, DHA reversed drug resistance and induced cytoprotective autophagy and ferroptosis by regulating the PI3K/AKT/Nrf2/GPX4 signalling pathway in PC3R cells. We propose that DHA could be developed as a chemosensitizer and that the PI3K/AKT /Nrf2/GPX4 signalling pathway might be a promising therapeutic target for overcoming cancer drug resistance.

• MeSH
• chemorezistence MeSH
• docetaxel farmakologie   MeSH
• epitelo-mezenchymální tranzice MeSH
• faktor 2 související s NF-E2 * metabolismus   farmakologie   MeSH
• fosfatidylinositol-3-kinasy metabolismus   farmakologie   MeSH
• kyseliny dokosahexaenové farmakologie   MeSH
• lidé MeSH
• nádory prostaty * farmakoterapie   MeSH
• protoonkogenní proteiny c-akt metabolismus   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Prostate cancer is one of the main causes of male cancer-related deaths worldwide and the suppression of androgen receptor signalling is established as an effective strategy for the treatment. A series of galeterone analogues including several steroid-fused azacycles, as well as 17-(benzimidazol-1-ylimino), 16α-(benzimidazol-2-ylamino), and 16α-(benzothiazol-2-ylamino) steroid derivatives, were synthesized and tested against prostate cancer cell lines. Candidate compound 3f was shown to reduce AR-regulated transcription in a dose-dependent manner in nanomolar ranges and suppress expression of AR-regulated proteins Nkx3.1 and PSA in 22Rv1-ARE14 and VCaP cancer cell lines. Flexible docking study revealed similar position of 3f within AR binding site in comparison of galeterone even with stronger binding energy.

• MeSH
• androstadieny chemická syntéza   chemie   farmakologie   MeSH
• benzimidazoly chemická syntéza   chemie   farmakologie   MeSH
• buněčné linie MeSH
• buňky PC-3 MeSH
• lidé MeSH
• molekulární struktura MeSH
• nádory prostaty farmakoterapie   metabolismus   patologie   MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky chemická syntéza   chemie   farmakologie   MeSH
• screeningové testy protinádorových léčiv MeSH
• viabilita buněk účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH