Benign prostatic hyperplasia (BPH) is a chronic male disease characterized by the enlarged prostate. Celtis chosenianaNakai (C. choseniana) is medicinally used to alleviate pain, gastric disease, and lung abscess. In this study, the effect of C. choseniana extract on BPH was investigated using testosterone-induced rats. Sprague Dawley rats were divided into five groups: control, BPH (testosterone 5 mg·kg^-1), Fina (finasteride 2 mg·kg^-1), and C. choseniana (50 and 100 mg·kg^-1). After four weeks of TP treatment with finasteride or C. choseniana, prostate weights and DHT levels were measured. In addition, the prostates were histopathologically examined and measured for protein kinase B (Akt)/nuclear factor-κB (NF-κB)/AR signaling, proliferation, apoptosis, and autophagy. Prostate weight and epithelial thickness were reduced in the C. choseniana groups compared with that in the BPH group. The extract of C. choseniana acted as a 5α reductase inhibitor, reducing DHT levels in the prostate. Furthermore, the extract of C. choseniana blocked the activation of p-Akt, nuclear NF-κB activation and reduced the expression of AR and PSA compared with BPH. Moreover, the expression of Bax, PARP-1, and p53 increased, while the expression of bcl-2 decreased. The present study demonstrated that C. choseniana extract alleviated testosterone-induced BPH by suppressing 5α reductase and Akt/NF-κB activation, reducing AR signaling and inducing apoptosis and autophagy in the prostate. These results suggested that C. choseniana probably contain potential herbal agents to alleviate BPH.
Animals ; Cholestenone 5 alpha-Reductase/metabolism* ; Finasteride/adverse effects* ; Male ; NF-kappa B/genetics* ; Plant Extracts/therapeutic use* ; Prostatic Hyperplasia/drug therapy* ; Proto-Oncogene Proteins c-akt/genetics* ; Rats ; Rats, Sprague-Dawley ; Receptors, Androgen/metabolism* ; Testosterone ; Ulmaceae/metabolism*

The development and progression of metastatic castration-resistant prostate cancer is the major challenge in the treatment of advanced prostate cancer. The androgen receptor signaling pathway remains active in metastatic castration-resistant prostate cancer. Docetaxel and cabazitaxel are the first- and second-line chemotherapy, respectively, for patients with metastatic castration-resistant prostate cancer. These two taxanes, in general, function by (i) inhibiting mitosis and inducing apoptosis and (ii) preventing microtubule-dependent cargo trafficking. In prostate cancer, taxanes have been reported to inhibit the nuclear translocation and activity of the androgen receptor. However, whether this is attainable or not clinically remains controversial. In this review, we will provide a comprehensive view of the effects of taxanes on androgen receptor signaling in prostate cancer.
Antineoplastic Agents, Phytogenic/therapeutic use* ; Humans ; Male ; Prostatic Neoplasms, Castration-Resistant/drug therapy* ; Receptors, Androgen/drug effects* ; Signal Transduction/drug effects* ; Taxoids/therapeutic use*

Therapy resistance is a significant challenge for prostate cancer treatment in clinic. Although targeted therapies such as androgen deprivation and androgen receptor (AR) inhibition are effective initially, tumor cells eventually evade these strategies through multiple mechanisms. Lineage reprogramming in response to hormone therapy represents a key mechanism that is increasingly observed. The studies in this area have revealed specific combinations of alterations present in adenocarcinomas that provide cells with the ability to transdifferentiate and perpetuate AR-independent tumor growth after androgen-based therapies. Interestingly, several master regulators have been identified that drive plasticity, some of which also play key roles during development and differentiation of the cell lineages in the normal prostate. Thus, further study of each AR-independent tumor type and understanding underlying mechanisms are warranted to develop combinational therapies that combat lineage plasticity in prostate cancer.
Androgen Antagonists/therapeutic use* ; Androgen Receptor Antagonists/therapeutic use* ; Gene Expression Regulation, Neoplastic ; Humans ; Male ; Prostatic Neoplasms/genetics* ; Prostatic Neoplasms, Castration-Resistant/genetics* ; Receptors, Androgen/drug effects*

Androgen receptor (AR) is a ligand-activated transcription factor that plays a pivotal role in the development and progression of many severe diseases such as prostate cancer, muscle atrophy, and osteoporosis. Binding of ligands to AR triggers the conformational changes in AR that may affect the recruitment of coactivators and downstream response of AR signaling pathway. Therefore, AR ligands have great potential to treat these diseases. In this study, we searched for novel AR ligands by performing a docking-based virtual screening (VS) on the basis of the crystal structure of the AR ligand binding domain (LBD) in complex with its agonist. A total of 58 structurally diverse compounds were selected and subjected to LBD affinity assay, with five of them (HBP1-3, HBP1-17, HBP1-38, HBP1-51, and HBP1-58) exhibiting strong binding to AR-LBD. The IC values of HBP1-51 and HBP1-58 are 3.96 µM and 4.92 µM, respectively, which are even lower than that of enzalutamide (Enz, IC = 13.87 µM), a marketed second-generation AR antagonist. Further bioactivity assays suggest that HBP1-51 is an AR agonist, whereas HBP1-58 is an AR antagonist. In addition, molecular dynamics (MD) simulations and principal components analysis (PCA) were carried out to reveal the binding principle of the newly-identified AR ligands toward AR. Our modeling results indicate that the conformational changes of helix 12 induced by the bindings of antagonist and agonist are visibly different. In summary, the current study provides a highly efficient way to discover novel AR ligands, which could serve as the starting point for development of new therapeutics for AR-related diseases.
Androgen Receptor Antagonists ; pharmacology ; Androgens ; metabolism ; pharmacology ; Biological Assay ; Cell Line, Tumor ; Drug Discovery ; methods ; Humans ; Ligands ; Male ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Phenylthiohydantoin ; analogs & derivatives ; pharmacology ; Principal Component Analysis ; Prostatic Neoplasms ; drug therapy ; Protein Binding ; physiology ; Protein Conformation ; drug effects ; Receptors, Androgen ; metabolism

Objective: To establish enzalutamide-resistant human prostate cancer cell lines and screen out the lncRNA and mRNA expression profiles associated with enzalutamide resistance. METHODS: Human prostate cancer cell lines LNCAP and C4-2B were cultured with 10 μmol/L enzalutamide for 6 months in vitro for the establishment of enzalutamide-resistant subclones LNCAP-ENZA and C4-2B-ENZA. The IC50 value and enzalutamide resistance index of each cell line were examined by MTT assay, the expressions of enzalutamide-related genes FL-AR, AR-V7 and HnRNPA1 were determined by Western blot, and the lncRNA and mRNA differential expressions of C4-2B and C4-2B-ENZA were detected by high-throughout lncRNA microarray. RESULTS: Compared with LNCAP and C4-2B, the IC50 values of enzalutamide-resistant subclones LNCAP-ENZA (60.83 μmol/L) and C4-2B-ENZA (88.32 μmol/L) were increased significantly (P < 0.05) and the enzalutamide-resistance indexes of the LNCAP-ENZA and C4-2B-ENZA cells were 4.94 and 4.67, respectively. The expressions of AR-V7 and HnRNPA1 were markedly up-regulated in the LNCAP-ENZA and C4-2B-ENZA cells as compared with those in the LNCAP and C4-2B cells, but that of FL-AR showed no significant change. A total of 1 440 lncRNAs and 1 236 mRNAs were identified as differentially expressed in the C4-2B-ENZA cells. CONCLUSIONS Enzalutamide -resistant human prostate cancer cell subclones LNCAP-ENZA and C4-2B-ENZA were successfully established and enzalutamide resistance-associated lncRNA and mRNA were identified, which may provide some molecular evidence for the management of enzalutamide-resistant human prostate cancer.
Cell Line, Tumor ; drug effects ; Drug Resistance, Neoplasm ; Humans ; Male ; Phenylthiohydantoin ; analogs & derivatives ; pharmacology ; Prostatic Neoplasms ; drug therapy ; genetics ; pathology ; RNA, Long Noncoding ; metabolism ; RNA, Messenger ; metabolism ; RNA, Neoplasm ; metabolism ; Receptors, Androgen

The epithelium of the human epididymis maintains an appropriate luminal environment for sperm maturation that is essential for male fertility. Regional expression of small noncoding RNAs such as microRNAs contributes to segment-specific gene expression and differentiated functions. MicroRNA profiles were reported in human epididymal tissues but not specifically in the epithelial cells derived from those regions. Here, we reveal miRNA signatures of primary cultures of caput, corpus, and cauda epididymis epithelial cells and of the tissues from which they were derived. We identify 324 epithelial cell-derived microRNAs and 259 tissue-derived microRNAs in the epididymis, some of which displayed regionalized expression patterns in cells and/or tissues. Caput cell-enriched miRNAs included miR-573 and miR-155. Cauda cell-enriched miRNAs included miR-1204 and miR-770. Next, we determined the gene ontology pathways associated with in silico predicted target genes of the differentially expressed miRNAs. The effect of androgen receptor stimulation on miRNA expression was also investigated. These data show novel epithelial cell-derived miRNAs that may regulate the expression of important gene networks that are responsible for the regionalized gene expression and function of the epididymis.
Adult ; Androgens/pharmacology* ; Computer Simulation ; Epididymis/metabolism* ; Epithelial Cells/metabolism* ; Epithelium/metabolism* ; Gene Expression Profiling ; Gene Regulatory Networks/drug effects* ; Humans ; Male ; MicroRNAs/genetics* ; Primary Cell Culture ; Receptors, Androgen/metabolism* ; Sequence Analysis, RNA

Objective: To investigate the influence of diethylstilbestrol (DES) on the mRNA expressions of the androgen receptor (AR), estrogen receptor α (ERα), proliferating cell nuclear antigen (PCNA), and actin alpha 1 (ACTα1) in the gubernaculums testis of newborn mice and explore their action mechanisms. METHODS: A total of 140 male Kunming mice were randomly divided into a blank control, a dimethyl sulfoxide (DMSO) control, and 5 experimental groups to be treated subcutaneously with normal saline, DMSO, and DES at 0.02, 0.1, 0.5, 10 and 50 μg per kg of the body weight per day, respectively, at gestation days 9－17. On the first day after birth, the animals were sacrificed and the gubernaculums testis collected for detection of the mRNA expressions of AR, ERα, PCNA and ACTα1 by RT-PCR. RESULTS: Compared with the DMSO control, the experimental groups, particularly the DES 10 and 50 μg groups, showed significant increases in the mRNA expression of ERα (RE2 = 0.825, P <0.05), but remarkable decreases in those of AR, PCNA and ACTα1 (RA2 = 0.713, RP2 = 0.946, RT2 = 0.960, P <0.01), all in a dose-dependent manner. CONCLUSIONS The AR, ERα, PCNA, and ACTα1 mRNA are expressed in the gubernaculum testis of normal newborn mice, and their expression levels may be influenced by intervention with different concentrations of DES during the gestation. Exogenous estrogens may affect the proliferation and contraction of gubernaculum testis cells and consequently the normal development of the testis or even the whole male reproductive system by influencing the metabolism of ER and/or AR.
Actins ; metabolism ; Animals ; Animals, Newborn ; Cells, Cultured ; Diethylstilbestrol ; pharmacology ; Dimethyl Sulfoxide ; pharmacology ; Estrogen Receptor alpha ; metabolism ; Estrogens, Non-Steroidal ; pharmacology ; Genitalia, Male ; Gubernaculum ; drug effects ; metabolism ; Male ; Mice ; Proliferating Cell Nuclear Antigen ; metabolism ; RNA, Messenger ; metabolism ; Random Allocation ; Receptors, Androgen ; metabolism ; Testis ; drug effects ; metabolism

OBJECTIVE: To investigate androgen receptor (AR) expression and the effect of epidermal growth factor (EGF) and testosterone on AR expression level.
 METHODS: EGF or different concentrations of testosterone were incubated with the primary urethral plate fibroblasts from patients with hypospadias. The levels of AR expression in the fibroblasts were detected by immunocytochemical assays and graphical analysis.
 RESULTS: There was no significant difference in AR activation under physiological concentrations (3×10(-8) mol/L) of testosterone between the control and the distal hypospadias group (P>0.05). However, there was a significant decrease in AR activation in the proximal hypospadias group compared to that in the control group (P<0.001). Under the concentration of 3×10(-6) mol/L, the effects of testosterone on AR activation were dramatically different in the three groups (control group>distal hypospadias group>proximal hypospadias group, P<0.001). AR activation level in the group of proximal hypospadias was improved most obviously when EGF and physiological concentration of testosterone were employed in the urethral plate fibroblasts from hypospadias patients (P<0.001), and it was improved more in the distal hypospadias group than that in the control group (P=0.02).
 CONCLUSION AR expression and activation in the urethral plate fibroblasts from hypospadias patients are abnormal. EGF can be used to improve AR activation in fibroblasts from different types of hypospadias, especially in the proximal type.
Cells, Cultured ; EGF Family of Proteins ; metabolism ; Fibroblasts ; drug effects ; metabolism ; Humans ; Hypospadias ; metabolism ; Male ; Receptors, Androgen ; metabolism ; Testosterone ; pharmacology

PURPOSE: To investigate the effects of anthocyanins extracted from black soybean, which have antioxidant activity, on apoptosis in vitro (in hormone refractory prostate cancer cells) and on tumor growth in vivo (in athymic nude mouse xenograft model). MATERIALS AND METHODS: The growth and viability of DU-145 cells treated with anthocyanins were assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and apoptosis was assessed by DNA laddering. Immunoblotting was conducted to evaluate differences in the expressions of p53, Bax, Bcl, androgen receptor (AR), and prostate specific antigen (PSA). To study the inhibitory effects of anthocyanins on tumor growth in vivo, DU-145 tumor xenografts were established in athymic nude mice. The anthocyanin group was treated with daily oral anthocyanin (8 mg/kg) for 14 weeks. After 2 weeks of treatment, DU-145 cells (2x106) were inoculated subcutaneously into the right flank to establish tumor xenografts. Tumor dimensions were measured twice a week using calipers and volumes were calculated. RESULTS: Anthocyanin treatment of DU-145 cells resulted in 1) significant increase in apoptosis in a dose-dependent manner, 2) significant decrease in p53 and Bcl-2 expressions (with increased Bax expression), and 3) significant decrease in PSA and AR expressions. In the xenograft model, anthocyanin treatment significantly inhibit tumor growth. CONCLUSION: This study suggests that anthocyanins from black soybean inhibit the progression of prostate cancer in vitro and in a xenograft model.
Animals ; Anthocyanins/*pharmacology ; Apoptosis/*drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Male ; Mice, Inbred C57BL ; Mice, Nude ; NAD/metabolism ; Prostate-Specific Antigen/metabolism ; Prostatic Neoplasms/genetics/*pathology ; Receptors, Androgen/metabolism ; Tumor Suppressor Protein p53/metabolism ; *Xenograft Model Antitumor Assays ; bcl-2-Associated X Protein/genetics/metabolism

To investigate the effect of compound Chinese traditional medicine PC-SPES II I in inhibiting proliferation of human prostate cancer cell LNCaP based on the androgen receptor (AR) signaling pathway. The effect of PC-SPES II on LNCaP cell proliferation was detected by MTT assay. According to the findings, at the mass concentration of 180-1 440 mg x L(-1), PC-SPES II significantly inhibited the proliferation of LNCaP cells; the IC50 of PC-SPES II at 24 h and 48 h were 311.48, 199.01 mg x L(-1), respectively. The flow Cytometry detection showed 240 mg x L(-1) PC-SPES II arrested cells in G2/M phase, and an obvious apoptotic peak appeared before G0/G1 peak and rose over time. Meanwhile, Hoechst 33258 staining revealed apoptotic cellular morphology. Annexin V-FITC/PI staining manifested an increase in apoptotic cell ratio at the PC-SPES II concentration of 480 mg x L(-1) in a dose dependent manner. The prostate specific antigen (PSA) secretion of LNCaP cells was tested by PSA ELISA kit. Besides, compared with 25 mg x L(-1) Bic, 480 mg x L(-1) PC-SPES II significantly reduced the cell secretion of PSA. The AR and PSA mRNA and protein expressions were detected by qRT-PCR and Western blot. According to the results, after the induction of LNCaP cells with synthetic androgen 25 μg x L(-1) R1881, 240-480 mg x L(-1) PC-SPES II notably down-regulated the AR and PSA mRNA and protein expressions and inhibited the translocation of AR from cytoplasm to nucleus. In summary, PC-SPES II significantly can inhibit the in vitro proliferation of LNCaP cells and arrest cell cycle arrest in G2/M phase. Its mechanism may be associated with the down-regulation of the AR and PSA expressions and the inhibition of AR nuclear translocation.
Antineoplastic Agents, Phytogenic ; pharmacology ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Drugs, Chinese Herbal ; pharmacology ; Humans ; Male ; Prostate-Specific Antigen ; genetics ; metabolism ; Prostatic Neoplasms ; drug therapy ; genetics ; metabolism ; physiopathology ; Receptors, Androgen ; genetics ; metabolism ; Signal Transduction ; drug effects