The androgen receptor can signal through Wnt/β-Catenin in prostate cancer cells as an adaptation mechanism to castration levels of androgens

<p>Abstract</p> <p>Background</p> <p>A crucial event in Prostate Cancer progression is the conversion from a hormone-sensitive to a hormone-refractory disease state. Correlating with this transition, androgen receptor (AR) amplification and mutations are often observed in patients failing hormonal ablation therapies. β-Catenin, an essential component of the canonical Wnt signaling pathway, was shown to be a coactivator of the AR signaling in the presence of androgens. However, it is not yet clear what effect the increased levels of the AR could have on the Wnt signaling pathway in these hormone-refractory prostate cells.</p> <p>Results</p> <p>Transient transfections of several human prostate cancer cell lines with the AR and multiple components of the Wnt signaling pathway demonstrate that the AR overexpression can potentiate the transcriptional activities of Wnt/β-Catenin signaling. In addition, the simultaneous activation of the Wnt signaling pathway and overexpression of the AR promote prostate cancer cell growth and transformation at castration levels of androgens. Interestingly, the presence of physiological levels of androgen or other AR agonists inhibits these effects. These observations are consistent with the nuclear co-localization of the AR and β-Catenin shown by immunohistochemistry in human prostate cancer samples. Furthermore, chromatin immunoprecipitation assays showed that Wnt3A can recruit the AR to the promoter regions of Myc and Cyclin D1, which are well-characterized downstream targets of the Wnt signalling pathway. The same assays demonstrated that the AR and β-Catenin can be recruited to the promoter and enhancer regions of a known AR target gene PSA upon Wnt signaling. These results suggest that the AR is promoting Wnt signaling at the chromatin level.</p> <p>Conclusion</p> <p>Our findings suggest that the AR signaling through the Wnt/β-Catenin pathway should be added to the well established functional interactions between both pathways. Moreover, our data show that via this interaction the AR could promote prostate cell malignancy in a ligand-independent manner.</p

Changes in Chromosomal Localization of Heterochromatin-binding Proteins during the Cell Cycle in Drosophila

We examined the heterochromatic binding of GAGA factor and proliferation disrupter (Prod) proteins during the cell cycle in Drosophila melanogaster and sibling species. GAGA factor binding to the brownDominant AG-rich satellite sequence insertion was seen at metaphase, however, no binding of GAGA factor to AG-rich sequences was observed at interphase in polytene or diploid nuclei. Comparable mitosis-specific binding was found for Prod protein to its target satellite in pericentric heterochromatin. At interphase, these proteins bind numerous dispersed sites in euchromatin, indicating that they move from euchromatin to heterochromatin and back every cell cycle. The presence of Prod in heterochromatin for a longer portion of the cell cycle than GAGA factor suggests that they cycle between euchromatin and heterochromatin independently. We propose that movement of GAGA factor and Prod from high affinity sites in euchromatin occurs upon condensation of metaphase chromosomes. Upon decondensation, GAGA factor and Prod shift from low affinity sites within satellite DNA back to euchromatic sites as a self-assembly process

The androgen receptor can signal through Wnt/β-Catenin in prostate cancer cells as an adaptation mechanism to castration levels of androgens-3

<p><b>Copyright information:</b></p><p>Taken from "The androgen receptor can signal through Wnt/β-Catenin in prostate cancer cells as an adaptation mechanism to castration levels of androgens"</p><p>http://www.biomedcentral.com/1471-2121/9/4</p><p>BMC Cell Biology 2008;9():4-4.</p><p>Published online 24 Jan 2008</p><p>PMCID:PMC2246119.</p><p></p>thout Wnt3A 100 ng/ml for four days in 96 well plates. The cells were then labeled with [H]-thymidine and harvested to measure the thymidine incorporation. Cells that received no DHT treatment were used as control. The percentage of [H]-thymidine incorporation was calculated compared with control. (B). LNCaP and LNCaP-Flag-AR cells were plated in soft agar with no treatment as control or with 100 ng/ml Wnt3A, or 10 nM DHT. After approximately 4 weeks, colonies were fixed with 10% formaldehyde in PBS. A representative field of cells was photographed for each cell type, with or without treatment using bright-field microscopy. Upper panel LNCaP or LNCaP-Flag-AR cells received no treatment, while lower panel, LNCaP-Flag-AR cells were either treated with Wnt3A or DHT

The androgen receptor can signal through Wnt/β-Catenin in prostate cancer cells as an adaptation mechanism to castration levels of androgens-4

<p><b>Copyright information:</b></p><p>Taken from "The androgen receptor can signal through Wnt/β-Catenin in prostate cancer cells as an adaptation mechanism to castration levels of androgens"</p><p>http://www.biomedcentral.com/1471-2121/9/4</p><p>BMC Cell Biology 2008;9():4-4.</p><p>Published online 24 Jan 2008</p><p>PMCID:PMC2246119.</p><p></p>n normal prostate tissues, the low levels of AR expression, compared with the high levels in prostate cancer cells, were indicated by lack of AR staining in cells (A); β-Catenin was predominantly located at the normal cytoplasmic membrane (B). In late stage prostate cancer samples, AR was substantially overexpressed in the nuclei of the prostate cancer cells (C) where nuclear β-Catenin staining was also observed in some of these cells (D)

The androgen receptor can signal through Wnt/β-Catenin in prostate cancer cells as an adaptation mechanism to castration levels of androgens-1

<p><b>Copyright information:</b></p><p>Taken from "The androgen receptor can signal through Wnt/β-Catenin in prostate cancer cells as an adaptation mechanism to castration levels of androgens"</p><p>http://www.biomedcentral.com/1471-2121/9/4</p><p>BMC Cell Biology 2008;9():4-4.</p><p>Published online 24 Jan 2008</p><p>PMCID:PMC2246119.</p><p></p>lates. 7 days after transfection, the number of cells was determined with a Guava proliferation assay. Cells transfected with GFP were used as control. The percentage of cell numbers was calculated for cells transfected with Wnt or AR or both compared with control samples. (B) AR expression and Flag-tagged AR in LNCaP-Flag-AR cells and LNCaP cells were detected by Western blot. Actin was used as loading control. (C). LNCaP cells and LNCaP-Flag-AR cells in phenol-red free RPMI with 5% charcoal-stripped serum were treated with 100 ng/ml Wnt3A for four days in 96 well plates. The cells were then labelled with [H]-thymidine and harvested to measure the amount of thymidine incorporation. LNCaP cells which received no Wnt3A treatment were used as control. The percentage of [H]-thymidine incorporation was calculated compared with control

The androgen receptor can signal through Wnt/β-Catenin in prostate cancer cells as an adaptation mechanism to castration levels of androgens-5

<p><b>Copyright information:</b></p><p>Taken from "The androgen receptor can signal through Wnt/β-Catenin in prostate cancer cells as an adaptation mechanism to castration levels of androgens"</p><p>http://www.biomedcentral.com/1471-2121/9/4</p><p>BMC Cell Biology 2008;9():4-4.</p><p>Published online 24 Jan 2008</p><p>PMCID:PMC2246119.</p><p></p>6 hours before cross-linking. Anti-β-Catenin (A, B, G and H) and anti-AR (C, D, E and F) antibodies, together with negative control IgG were then used for immunoprecipitation. After reverse crosslinking and DNA purification, PCR products were analyzed using the Agilent 2100 bioanalyzer. Percent of input is shown here to compare the levels of β-Catenin or AR at the promoter or enhancer region of PSA, or the promoter region of Cyclin D1 or Myc

Molecular subtyping reveals immune alterations associated with progression of bronchial premalignant lesions

Bronchial premalignant lesions can potentially progress to lung squamous cell carcinoma. Here, the authors profile bronchial biopsies from high-risk smokers by RNA sequencing and identify four molecular subtypes of premalignant lesions and an immune molecular signature that associates with lesion progression

Discovery and Pharmacological Characterization of JNJ-42756493 (Erdafitinib), a Functionally Selective Small-Molecule FGFR Family Inhibitor

©2017 American Association for Cancer Research. Fibroblast growth factor (FGF) signaling plays critical roles in key biological processes ranging from embryogenesis to wound healing and has strong links to several hallmarks of cancer. Genetic alterations in FGF receptor (FGFR) family members are associated with increased tumor growth, metastasis, angiogenesis, and decreased survival. JNJ-42756493, erdafitinib, is an orally active small molecule with potent tyrosine kinase inhibitory activity against all four FGFR family members and selectivity versus other highly related kinases. JNJ-42756493 shows rapid uptake into the lysosomal compartment of cells in culture, which is associated with prolonged inhibition of FGFR signaling, possibly due to sustained release of the inhibitor. In xenografts from human tumor cell lines or patient-derived tumor tissue with activating FGFR alterations, JNJ-42756493 administration results in potent and dose-dependent antitumor activity accompanied by pharmacodynamic modulation of phospho-FGFR and phospho-ERK in tumors. The results of the current study provide a strong rationale for the clinical investigation of JNJ- 42756493 in patients with tumors harboring FGFR pathway alterations