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Background Androgen receptor (AR) plays important role in the development, progression, and metastasis of prostate cancer (PCa). Caffeic acid phenethyl ester (CAPE) is the main component of honey bee propolis. We determined if CAPE affects the signaling and stability of AR in PCa cells. Methods Effects of CAPE on AR transcriptional activity and localization were determined by reporter gene assay and immunofluorescent microscopy. Western blotting, fluorescent polarization, computer simulation, and animal experiment were performed to investigate the molecular mechanism how CAPE reduces the stability of AR. Results CAPE treatment dose-dependently suppressed the transcriptional activity of AR as well as the protein levels of AR and its target gene PSA. Cyclohexamide treatment revealed that androgen stabilized AR protein, but AR stability was diminished by CAPE. Fluorescence microscopy demonstrated that androgen promoted the nucleus translocation of AR in PCa cells, while treatment with CAPE reduced protein level of AR in both nucleus and cytoplasm. CAPE treatment suppressed the phosphorylation of Ser81 and Ser213 on AR, which regulates the stability of AR. CDK1 and AKT are the kinases phosphorylating Ser81 and Ser213 on AR, respectively. CAPE treatment significantly reduced the protein level and activity of CDK1 and AKT in PCa cells. Overexpression of CDK1 or AKT rescued the AR protein level under CAPE treatment. Conclusions Our results suggested that CAPE treatment reduced AR stability and AR transcriptional activity in PCa cells, implying the possibility of using CAPE as a treatment for advanced PCa. Graphical abstract Electronic supplementary material The online version of this article (10.1186/s12964-019-0404-9) contains supplementary material, which is available to authorized users.

Androgen receptor (AR), an androgen-activated transcription factor, belongs to the nuclear receptor superfamily. AR plays an important role in the development and progression of prostate cancer (PCa). However, the role of AR in PCa metastasis is not fully understood. To investigate the role of AR in PCa metastasis, we examined AR expression level in primary and metastatic PCa by analyzing gene array data of 378 primary prostate tumors and 120 metastatic prostate tumors from Oncomine, as well as carrying out immunohistochemical (IHC) staining of 56 prostate cancer samples. Expression of mRNA and protein of AR as well as its target gene prostate-specific antigen (PSA) was much higher in metastatic prostate tumors than in primary prostate tumors. Knockdown of AR with siRNA or treating with anti-androgen Casodex reduced migration and invasion ability of C4-2B PCa cells. Knockdown of AR increased protein expression of E-cadherin and AR coregulator KAT5 but reduced expression of epithelial-mesenchymal transition (EMT) marker proteins Slug, Snail, MMP-2, vimentin, and β-catenin. Knockdown of KAT5 increased migration of C4-2B cells, whereas overexpression of KAT5 suppressed cell migration. KAT5 knockdown rescues the suppressive effect of AR knockdown on migration of C4-2B cells. Gene expression level of AR and KAT5 showed a negative correlation. PCa patients with higher AR expression or lower KAT5 expression correlated with shorter recurrence-free survival. Our study suggested that elevation of AR expression and AR signaling in prostate tumors promotes PCa metastasis by induction of EMT and reduction of KAT5.

Background Androgen ablation therapy is the primary treatment for metastatic prostate cancer (PCa). However, the majority of PCa patients receiving the androgen deprivation therapy develop recurrent castration-resistant prostate cancer (CRPC) within two years. Chemotherapies show little effect on prolonging survival of CRPC patients and new treatments are needed. Previous studies reported that the extracts from rooibos (Aspalathus linearis) exhibit chemopreventive properties in some cancer models, including skin, liver and oesophagus cancers in animals. We therefore investigate if extracts from rooibos can suppress the proliferation of CRPC cells. Purpose We investigated whether an aspalathin-rich green rooibos extract (GRT™; 12.78 g aspalathin/100 g extract) demonstrates anti-cancer activity against CRPC cells. Methods High performance liquid chromatography (HPLC) was used to profile the major flavonoids in GRT. Hoechst-dye proliferation assay, 3,4,5-dimethylthiazol-2-yl)-2-5-diphenyltetrazolium bromide (MTT) viability assay and flow cytometry assay were used to explore the effects of GRT on the proliferation and cell cycle progression of CRPC cells. Comet assay was used to survey whether GRT induces apoptosis in CRPC cells. LNCaP 104-R1 xenograft nude mice model was used to determine the inhibitory effect of GRT on CRPC tumors in vivo. Micro-Western Array (MWA) and Western blot analysis were carried out to unravel the underlying molecular mechanism. Results GRT contained aspalathin as the most abundant flavonoid. GRT suppressed the proliferation and survival of LNCaP 104-R1, LNCaP FGC and PC-3 PCa cells. Flow cytometry analysis showed that GRT decreased the population of PCa cells in S phase but increased the cell population in G2/M phase. Comet assay confirmed that GRT induced apoptosis in LNCaP 104-R1 cells. Gavage of 400 mg/kg GRT suppressed LNCaP 104-R1 xenografts in castrated nude mice. MWA and Western blot analysis indicated that GRT treatment suppressed Akt1, phospho-Akt Ser473, Cdc2, Bcl-2, TRAF4 and Aven, but increased activated Caspase 3, cytochrome c, and p27Kip1. Overexpression of Akt rescued the suppressive effects of GRT on CRPC cells. Co-treatment of GRT with Bcl-2 inhibitor ABT-737, PI3K inhibitor LY294002 and Akt inhibitor GSK 690693 exhibited additive inhibitory effect on proliferation of CRPC cells. Conclusions GRT suppresses the proliferation of CRPC cells via inhibition of Akt signaling.

The qRT-PCR analysis of 139 clinical samples and analysis of 150 on-line database clinical samples indicated that AKT3 mRNA expression level was elevated in primary prostate tumors. Immunohistochemical staining of 65 clinical samples revealed that AKT3 protein expression was higher in prostate tumors of stage I, II, III as compared to nearby normal tissues. Plasmid overexpression of AKT3 promoted cell proliferation of LNCaP, PC-3, DU-145, and CA-HPV-10 human prostate cancer (PCa) cells, while knockdown of AKT3 by siRNA reduced cell proliferation. Overexpression of AKT3 increased the protein expression of total AKT, phospho-AKT S473, phospho-AKT T308, B-Raf, c-Myc, Skp2, cyclin E, GSK3β, phospho-GSK3β S9, phospho-mTOR S2448, and phospho-p70S6K T421/S424, but decreased TSC1 (tuberous sclerosis 1) and TSC2 (tuberous Sclerosis Complex 2) proteins in PC-3 PCa cells. Overexpression of AKT3 also increased protein abundance of phospho-AKT S473, phospho-AKT T308, and B-Raf but decreased expression of TSC1 and TSC2 proteins in LNCaP, DU-145, and CA-HPV-10 PCa cells. Oncomine datasets analysis suggested that AKT3 mRNA level was positively correlated to BRAF. Knockdown of AKT3 in DU-145 cells with siRNA increased the sensitivity of DU-145 cells to B-Raf inhibitor treatment. Knockdown of TSC1 or TSC2 promoted the proliferation of PCa cells. Our observations implied that AKT3 may be a potential therapeutic target for PCa treatment.

Head and neck cancers, which affect 650,000 people and cause 350,000 deaths per year, is the sixth leading cancer by cancer incidence and eighth by cancer-related death worldwide. Oral cancer is the most common type of head and neck cancer. More than 90% of oral cancers are oral and oropharyngeal squamous cell carcinoma (OSCC). The overall five-year survival rate of OSCC patients is approximately 63%, which is due to the low response rate to current therapeutic drugs. In this review we discuss the possibility of using caffeic acid phenethyl ester (CAPE) as an alternative treatment for oral cancer. CAPE is a strong antioxidant extracted from honeybee hive propolis. Recent studies indicate that CAPE treatment can effectively suppress the proliferation, survival, and metastasis of oral cancer cells. CAPE treatment inhibits Akt signaling, cell cycle regulatory proteins, NF-κB function, as well as activity of matrix metalloproteinase (MMPs), epidermal growth factor receptor (EGFR), and Cyclooxygenase-2 (COX-2). Therefore, CAPE treatment induces cell cycle arrest and apoptosis in oral cancer cells. According to the evidence that aberrations in the EGFR/phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling, NF-κB function, COX-2 activity, and MMPs activity are frequently found in oral cancers, and that the phosphorylation of Akt, EGFR, and COX-2 correlates to oral cancer patient survival and clinical progression, we believe that CAPE treatment will be useful for treatment of advanced oral cancer patients.

Caffeic acid phenethyl ester (CAPE) is a bioactive component extracted from honeybee hive propolis. Our observations indicated that CAPE treatment suppressed cell proliferation and colony formation of TW2.6 human oral squamous cell carcinoma (OSCC) cells dose-dependently. CAPE treatment decreased G1 phase cell population, increased G2/M phase cell population, and induced apoptosis in TW2.6 cells. Treatment with CAPE decreased protein abundance of Akt, Akt1, Akt2, Akt3, phospho-Akt Ser473, phospho-Akt Thr 308, GSK3β, FOXO1, FOXO3a, phospho-FOXO1 Thr24, phospho-FoxO3a Thr32, NF-κB, phospho-NF-κB Ser536, Rb, phospho-Rb Ser807/811, Skp2, and cyclin D1, but increased cell cycle inhibitor p27Kip. Overexpression of Akt1 or Akt2 in TW2.6 cells rescued growth inhibition caused by CAPE treatment. Co-treating TW2.6 cells with CAPE and 5-fluorouracil, a commonly used chemotherapeutic drug for oral cancers, exhibited additive cell proliferation inhibition. Our study suggested that administration of CAPE is a potential adjuvant therapy for patients with OSCC oral cancer.

The anti-oxidative and anti-inflammatory activities of two different species of traditional Chinese medicines that shared the same name have been studied. The extracts of Glycine radix have higher activities in free radical-scavenging activity determined with DPPH, reduction in hemoglobin-catalyzed lipid auto-oxidation and inhibition of the lipoxygenase (LOX) and cyclooxygenase (COX)-catalyzed arachidonate oxidation compared to the activities of extract of Flemingia. One of the significant bioactive constituents of Glycine radix has been isolated and identified as daidzein.

The physician assistant (PA) is a relatively new medical specialty that developed to manage the shortage of resident physicians and to ensure that patients receive high-quality health care in today's increasingly complex and demanding medical environment. PAs in Taiwan are not governed by laws and regulations, and the absence of legislation to define their roles and responsibilities can lead to confusion in the work environment and potential communication barriers with coworkers and supervising physicians. The purpose of this exploratory study was to examine the environmental and sociodemographic factors that influence job satisfaction and job-related communication among PAs in Taiwan. The data source, a self-administered mail survey, was sent to 196 PAs working within medical facilities in northern, central, and southern Taiwan. The response rate to the survey was 71.01%. There was a strong correlation between communication satisfaction and job satisfaction among respondents. The PAs’ overall position in the hospital, relationships with coworkers (doctors, nurses, and other medical staff), and ability to perform his or her duties while working with the supervising physician were the major environmental factors that influenced job and communication satisfaction. In addition, the number of working years and marital status were important demographic factors influencing job satisfaction. Demographic and environmental factors influencing job satisfaction are analyzed, and ways in which the roles and responsibilities of PAs can be clarified, strengthened, and improved are discussed in an overall effort to provide management strategies for the current PA system in Taiwan.

By oligo microarray expression profiling, we identified a rice RING zinc-finger protein (RZFP), OsRZFP34, whose gene expression increased with high temperature or abscisic acid (ABA) treatment. As compared with the wild type, rice and Arabidopsis with OsRZFP34 overexpression showed increased relative stomata opening even with ABA treatment. Furthermore, loss-of-function mutation of OsRZFP34 and AtRZFP34 (At5g22920), an OsRZFP34 homolog in Arabidopsis, decreased relative stomata aperture under nonstress control conditions. Expressing OsRZFP34 in atrzfp34 reverted the mutant phenotype to normal, which indicates a conserved molecular function between OsRZFP34 and AtRZFP34. Analysis of water loss and leaf temperature under stress conditions revealed a higher evaporation rate and cooling effect in OsRZFP34-overexpressing Arabidopsis and rice than the wild type, atrzfp34 and osrzfp34. Thus, stomata opening, enhanced leaf cooling, and ABA insensitivity was conserved with OsRZFP34 expression. Transcription profiling of transgenic rice overexpressing OsRZFP34 revealed many genes involved in OsRZFP34-mediated stomatal movement. Several genes upregulated or downregulated in OsRZFP34-overexpressing plants were previously implicated in Ca(2+) sensing, K(+) regulator, and ABA response. We suggest that OsRZFP34 may modulate these genes to control stomata opening.

Prostate cancer is the fifth most common cancer overall in the world. Androgen ablation therapy is the primary treatment for metastatic prostate cancer. However, most prostate cancer patients receiving the androgen ablation therapy ultimately develop recurrent castration-resistant tumors within 1–3 years after treatment. The median overall survival time is 1–2 years after tumor relapse. Chemotherapy shows little effect on prolonging survival for patients with metastatic hormone-refractory prostate cancer. More than 80% of prostate tumors acquire mutation or deletion of tumor suppressor phosphatase and tensin homolog (PTEN), a negative regulator of PI3K/Akt signaling, indicating that inhibition of PI3K/Akt might be a potential therapy for advanced prostate tumors. Caffeic acid phenethyl ester (CAPE) is a strong antioxidant extracted from honeybee hive propolis. CAPE is a well-known NF-κB inhibitor. CAPE has been used in folk medicine as a potent anti-inflammatory agent. Recent studies indicate that CAPE treatment suppresses tumor growth and Akt signaling in human prostate cancer cells. We discuss the potential of using CAPE as a treatment for patients with advanced prostate cancer targeting Akt signaling pathway in this review article.

Oxysterols are oxidation products of cholesterol. Cholestane-3β, 5α, 6β-triol (abbreviated as triol) is one of the most abundant and active oxysterols. Here, we report that triol exhibits anti-cancer activity against human prostate cancer cells. Treatment of cells with triol dose-dependently suppressed proliferation of LNCaP CDXR-3, DU-145, and PC-3 human prostate cancer cells and reduced colony formation in soft agar. Oral administration of triol at 20 mg/kg daily for three weeks significantly retarded the growth of PC-3 xenografts in nude mice. Flow cytometric analysis revealed that triol treatment at 10-40 µM caused G1 cell cycle arrest while the TUNEL assay indicated that triol treatment at 20-40 µM induced apoptosis in all three cell lines. Micro-Western Arrays and traditional Western blotting methods indicated that triol treatment resulted in reduced expression of Akt1, phospho-Akt Ser473, phospho-Akt Thr308, PDK1, c-Myc, and Skp2 protein levels as well as accumulation of the cell cycle inhibitor p27(Kip). Triol treatment also resulted in reduced Akt1 protein expression in PC-3 xenografts. Overexpression of Skp2 in PC-3 cells partially rescued the growth inhibition caused by triol. Triol treatment suppressed migration and invasion of DU-145, PC-3, and CDXR-3 cells. The expression levels of proteins associated with epithelial-mesenchymal transition as well as focal adhesion kinase were affected by triol treatment in these cells. Triol treatment caused increased expression of E-cadherin protein levels but decreased expression of N-cadherin, vimentin, Slug, FAK, phospho-FAK Ser722, and phospho-FAK Tyr861 protein levels. Confocal laser microscopy revealed redistribution of β-actin and α-tubulin at the periphery of the CDXR-3 and DU-145 cells. Our observations suggest that triol may represent a promising therapeutic agent for advanced metastatic prostate cancer.