Pro-metastatic activity of AGR2 interrupts angiogenesis target bevacizumab efficiency via direct interaction with VEGFA and activation of NF-κB pathway.

Anterior gradient 2 (AGR2), an endoplasmic reticulum (ER)-resident protein-disulfide isomerase (PDI), is associated with cancer development and malignant progression. Here, we show that high level of AGR2 promotes the aggressive phenotype of prostate cancer (PCa) mouse models developed by either patient-derived xenografts or surgical intra-prostate implantation of PCa cells, associated with enrichment of the blood vessel network in tumor tissues. Angiogenesis markers VEGFR2 and CD34, accompanied with the invasive marker Vimentin, were predominantly stained in metastatic liver tissues.

Bisbibenzyls, novel proteasome inhibitors, suppress androgen receptor transcriptional activity and expression accompanied by activation of autophagy in prostate cancer LNCaP cells.

Context: Bisbibenzyl compounds have gained our interests for their potential antitumor activity in malignant cell-types.

Objective: The objective of this study is to investigate the effect of bisbibenzyl compounds riccardin C (RC), marchantin M (MM), and riccardin D (RD) on androgen receptor (AR) in prostate cancer (PCa) cells.

Materials And Methods: After exposure to 10 μM of the compounds for 24 h, cell cycle and cell survival analyses were performed using FACS and MTT assay to confirm the effect of these bisbibenzyls on PCa LNCaP cells.

Regulation of SOD2 and β-arrestin1 by interleukin-6 contributes to the increase of IGF-1R expression in docetaxel resistant prostate cancer cells.

Although several mechanisms behind resistance to docetaxel in castration-refractory prostate cancer (CRPC) have been investigated, molecular determinants of evolved resistance are still not entirely understood. Proteomics-based analysis in this study revealed that SOD2, associated with downregulation of reactive oxygen species (ROS), was significantly up-regulated in docetaxel-resistant (PC3/Doc) cells if compared to sensitive cells, and the expression of redox-regulated genes such as IGF-1R, CXCR4, and BCL2 was increased as well. Forced expression of SOD2 in sensitive cells led to the increase of IGF-1R and association with drug resistance, whereas silencing of SOD2 resulted in the decrease of IGF-1R at the protein level in resistant cells.

Differential regulation of MMPs by E2F1, Sp1 and NF-kappa B controls the small cell lung cancer invasive phenotype.

Background: E2F1 transcription factor plays a vital role in the regulation of diverse cellular processes including cell proliferation, apoptosis, invasion and metastasis. E2F1 overexpression has been demonstrated in small cell lung cancer (SCLC), and extensive metastasis in early phase is the most important feature of SCLC. In this study, we investigated the involvement of E2F1 in the process of invasion and metastasis in SCLC by regulating the expression of matrix metalloproteinases (MMPs).

Preclinical evaluation of the supercritical extract of azadirachta indica (neem) leaves in vitro and in vivo on inhibition of prostate cancer tumor growth.

Azadirachta indica, commonly known as neem, has gained worldwide prominence because of its medical properties, namely antitumor, antiviral, anti-inflammatory, antihyperglycemic, antifungal, and antibacterial activities. Despite these promising results, gaps remain in our understanding of the molecular mechanism of action of neem compounds and their potential for use in clinical trials. We investigated supercritical extract of neem leaves (SENL) for the following: molecular targets in vitro, in vivo efficacy to inhibit tumor growth, and bioactive compounds that exert antitumor activity.

Riccardin D Exerts Its Antitumor Activity by Inducing DNA Damage in PC-3 Prostate Cancer Cells In Vitro and In Vivo.

We recently reported that Riccardin D (RD) was able to induce apoptosis by targeting Topo II. Here, we found that RD induced cell cycle arrest in G2/M phase in PC-3 cells, and caused remarkable DNA damage as evidenced by induction of γH2AX foci, micronuclei, and DNA fragmentation in Comet assay. Time kinetic and dose-dependent studies showed that ATM/Chk2 and ATR/Chk1 signaling pathways were sequentially activated in response to RD.

Retigeric acid B-induced mitophagy by oxidative stress attenuates cell death against prostate cancer cells in vitro.

Aim: Retigeric acid B (RAB), a pentacyclic triterpenic acid from Lobaria kurokawae Yoshim, has been found to induce apoptosis in prostate cancer cells. The aim of this study was to investigate the roles of mitochondrial damage-caused mitophagy in RAB-induced prostate cancer cell death in vitro.

Methods: Human prostate cancer PC3 and LNCaP cells were tested.

Induction of DNA damage and ATF3 by retigeric acid B, a novel topoisomerase II inhibitor, promotes apoptosis in prostate cancer cells.

Retigeric acid B (RB) has been reported to exhibit its anti-tumor activity in vitro and in vivo. Here, we found that RB significantly inhibited activity of topoisomerase IIα (Topo IIα), leading to remarkable DNA damage in prostate cancer (PCa) cells as evidenced by a strong induction of γH2AX and DNA fragmentation. Activation of ATM and ATR sequentially led to induction of phospho-Chk1/2 and phospho-Cdc25 in response to RB.

Phenethyl isothiocyanate inhibits androgen receptor-regulated transcriptional activity in prostate cancer cells through suppressing PCAF.

Scope: Androgen receptor (AR) signaling is critical for all aspects of prostate growth and tumorigenesis. The glucosinolate-derived phenethyl isothiocyanate (PEITC) has recently been demonstrated to reduce the risk of prostate cancer (PCa) and inhibit PCa cell growth. We previously reported that p300/CBP-associated factor (PCAF), a co-regulator for AR, is upregulated in PCa cells through suppression of the mir-17 gene.

Retigeric acid B exhibits antitumor activity through suppression of nuclear factor-κB signaling in prostate cancer cells in vitro and in vivo.

Previously, we reported that retigeric acid B (RB), a natural pentacyclic triterpenic acid isolated from lichen, inhibited cell growth and induced apoptosis in androgen-independent prostate cancer (PCa) cells. However, the mechanism of action of RB remains unclear. In this study, we found that using PC3 and DU145 cells as models, RB inhibited phosphorylation levels of IκBα and p65 subunit of NF-κB in a time- and dosage-dependent manner.

Global methylation profiling for risk prediction of prostate cancer.

Purpose: The aim of this study was to investigate the promoter hypermethylation as diagnostic markers to detect malignant prostate cells and as prognostic markers to predict the clinical recurrence of prostate cancer.

Experimental Design: DNA was isolated from prostate cancer and normal adjacent tissues. After bisulfite conversion, methylation of 14,495 genes was evaluated using the Methylation27 microarrays in 238 prostate tissues.

Knockdown of AGR2 induces cellular senescence in prostate cancer cells.

Anterior-gradient 2 (AGR2), overexpressed in many tumors including prostate cancer (PCa), is implicated in stimulation of cell proliferation, adhesion, anti-apoptosis and cell cycle regulation. Here, a potential role of AGR2 in cellular senescence was investigated. We first observed that AGR2 was overexpressed in Chinese Han PCa tissues and had a positive correlation with cyclin D1 and p-Rb but not with p16(INK4a).

Antiangiogenic Effects and Therapeutic Targets of Azadirachta indica Leaf Extract in Endothelial Cells.

Azadirachta indica (common name: neem) leaves have been found to possess immunomodulatory, anti-inflammatory and anti-carcinogenic properties. The present study evaluates anti-angiogenic potential of ethanol extract of neem leaves (EENL) in human umbilical vein endothelial cells (HUVECs). Treatment of HUVECs with EENL inhibited VEGF induced angiogenic response in vitro and in vivo.

miR-141 modulates androgen receptor transcriptional activity in human prostate cancer cells through targeting the small heterodimer partner protein.

Background: Aberrant expressions of microRNAs, including upregulation of miR-141, are closely associated with the tumorigenesis of prostate cancer (PCa). The orphan receptor small heterodimer partner (Shp) is a co-repressor to androgen receptor (AR) and represses AR-regulated transcriptional activity.

Methods: Here, we investigated the correlation of Shp expression with the cellular level of miR-141 and its effects on AR transcriptional activity in non-malignant and malignant human prostate epithelial cell lines.

Vitamin d, sunlight and prostate cancer risk.

Prostate cancer is the second common cancer in men worldwide. The prevention of prostate cancer remains a challenge to researchers and clinicians. Here, we review the relationship of vitamin D and sunlight to prostate cancer risk.

Novel molecular targets of Azadirachta indica associated with inhibition of tumor growth in prostate cancer.

Advanced prostate cancer has significant long-term morbidity, and there is a growing interest in alternative and complimentary forms of therapy that will improve the outcomes of patients. Azadirachta indica (common name: neem) contains multiple active compounds that have potent anti-inflammatory and anticancer properties. The present study investigates the novel targets of the anticancer activity of ethanol extract of neem leaves (EENL) in vitro and evaluates the in vivo efficacy in the prostate cancer models.

Autophagy inhibition promotes paclitaxel-induced apoptosis in cancer cells.

Paclitaxel has been demonstrated to be an effective mitotic inhibitor and apoptosis inducer to treat aggressive malignancies. In this paper, we have provided a line of evidence that promotion of apoptotic cell death by paclitaxel was accompanied with induction of autophagy in A549 cells. Paclitaxel treatment could lead to the formation of acidic vesicular organelles (AVOs), the induction of Atg5, Beclin 1 and microtubule-associated protein 1 light chain 3 (LC3) expressions, and the increase of punctate fluorescent signals in A549 cells pre-transfected with green fluorescent protein (GFP)-tagged LC3.

Sesquiterpenoids from myrrh inhibit androgen receptor expression and function in human prostate cancer cells.

Aim: To examine whether two naturally occurring sesquiterpenoids (ST1 and ST2) with anti-proliferative activity in prostate cancer cells inhibit androgen receptor (AR) signaling.

Methods: Human prostate cancer cell lines LNCaP and PC3 were used. The expression of AR, AR translocation into the nucleus, and expression levels of AR coactivators ARA70 and steroid receptor coactivator-1 (SRC-1) in LNCaP cells were examined using real-time PCR and Western blot.

Associations of saposin C, Src, and androgen receptor upregulate the expression and function of androgen receptor in human prostate cancer cells.

We previously demonstrated that ectopic expression of neurotrophic peptide (NP) derived from saposin C promotes androgen receptor (AR) expression and transactivation in human prostate cancer cells. This prompted us to investigate how NP or saposin C can function in cells. We constructed plasmids expressing saposin C or a chimeric peptide of a viral TAT transduction domain and saposin C (TAT-saposin C) with His-tag.

A novel anticancer agent, retigeric acid B, displays proliferation inhibition, S phase arrest and apoptosis activation in human prostate cancer cells.

Retigeric acid B (RB), a naturally occurring pentacyclic triterpenic acid, has been noted for its antifungal properties in vitro. Here, we observed that RB inhibited prostate cancer cell proliferation and induced cell death in a dose-dependent manner, but exerted very little inhibitory effect on noncancerous prostate epithelial cell viability. Treatment of androgen-independent PC-3 cells with RB caused a moderate increase in p21(Cip1), and enforced the cell cycle arrest in the S phase.

Oxidative stress and DNA methylation in prostate cancer.

The protective effects of fruits, vegetables, and other foods on prostate cancer may be due to their antioxidant properties. An imbalance in the oxidative stress/antioxidant status is observed in prostate cancer patients. Genome oxidative damage in prostate cancer patients is associated with higher lipid peroxidation and lower antioxidant levels.

MicroRNAs and prostate cancer.

MicroRNAs (miRNAs) are a class of small, non-coding, single-stranded RNAs that negatively regulate gene expression by mainly binding to 30 untranslated region (UTR) of target mRNAs at the post-transcriptional level. Recent studies have demonstrated that aberrant expressions of miRNAs are closely associated with the development, invasion, metastasis and prognosis of various cancers including prostate cancer (PCa). The proposed molecular mechanisms that underlie the aberrant expression of miRNAs result from gene changes, epigenetic modification and alteration of Dicer abundance.

Vitamins and prostate cancer risk.

Prostate cancer (PC) is the second most common cancer in men worldwide. Its prevention and treatment remain a challenge to clinicians. Here we review the relationship of vitamins to PC risk.

Suppression of the androgen receptor function by quercetin through protein-protein interactions of Sp1, c-Jun, and the androgen receptor in human prostate cancer cells.

We have previously reported that the increase in c-Jun expression induced by quercetin inhibited androgen receptor (AR) transactivation, and Sp1 was involved in quercetin-mediated downregulation of AR activity. Transient transfection assays in this work revealed that co-expression of c-Jun quenched Sp1-induced production of luciferase activity driven by AR promoter or three copies of Sp1 binding elements in the AR promoter. Moreover, c-Jun repressed AR-mediated luciferase activity via androgen-response elements (AREs) of the hK2 gene, while this suppression could be restored partially by cotransfection of Sp1 expression plasmid.

Epigenetic regulation of Myc on retinoic acid receptor beta and PDLIM4 in RWPE1 cells.

Background: Hypermethylation of CpG islands is a common epigenetic alteration associated with cancer. Tumor suppressor genes retinoic acid receptor beta (RARbeta) and PDLIM4 are hypermethylated and silenced in prostate cancer (PCa) tissues and PCa cell lines compared to normal prostate cells.

Methods: In this study, a benign prostate epithelial cell line RWPE1 was used as a model to study the epigenetic regulation of Myc on the RARbeta and PDLIM4 promoters.