Reduced-folate carrier (RFC) is expressed in placenta and yolk sac,as well as in cells of the developing forebrain,hindbrain, neural tube,craniofacial region,eye, limb buds and heart

Background  

Folate is essential for cellular proliferation and tissue regeneration. As mammalian cells cannot synthesize folates de novo, tightly regulated cellular uptake processes have evolved to sustain sufficient levels of intracellular tetrahydrofolate cofactors to support biosynthesis of purines, pyrimidines, and some amino acids (serine, methionine). Though reduced-folate carrier (RFC) is one of the major proteins mediating folate transport, knowledge of the developmental expression of RFC is lacking. We utilized in situ hybridization and immunolocalization to determine the developmental distribution of RFC message and protein, respectively.     

Predicting iron and folate deficiency anaemias from standard blood testing: the mechanism and implications for clinical medicine and public health in developing countries

Background  

Developing countries have high prevalence of diseases, but facilities to diagnose and treat them are limited. We must use available resources in ways not needed where there are sophisticated equipment and trained staff. Anaemia is common; iron deficiency affects health and productivity; folate deficiency in pregnant women causes foetal abnormalities. Few developing countries can measure serum folate or ferritin, but standard automated blood analyses are widely available and can help predict folate and iron deficiency. The RDW-CV% (coefficient of variation of the red cell width) measures the variability in the size of red blood cells (RBC) in routine automated analysis of blood cells, but is seldom reported. Levels of RDW-CV% and haemoglobin (Hb) can predict iron deficiency anaemia.     

Depletion of the histone chaperone tNASP inhibits proliferation and induces apoptosis in prostate cancer PC-3 cells

Background  

NASP (Nuclear Autoantigenic Sperm Protein) is a histone chaperone that is present in all dividing cells. NASP has two splice variants: tNASP and sNASP. Only cancer, germ, transformed, and embryonic cells have a high level of expression of the tNASP splice variant. We examined the consequences of tNASP depletion for prostate cancer PC-3 cells.     

Growth inhibition of androgen-responsive prostate cancer cells with brefeldin A targeting cell cycle and androgen receptor

Background  

Androgen ablation is one of the viable therapeutic options for patients with primary hormone (androgen)-dependent prostate cancer. However, an antibiotic brefeldin A (BFA) has been shown to exhibit the growth inhibitory effect on human cancer cells. We thus investigated if BFA might inhibit proliferation of androgen-responsive prostate cancer LNCaP cells and also explored how it would be carried out, focusing on cell cycle and androgen receptor (AR).     

The evolutionary impact of androgen levels on prostate cancer in a multi-scale mathematical model

Background  

Androgens bind to the androgen receptor (AR) in prostate cells and are essential survival factors for healthy prostate epithelium. Most untreated prostate cancers retain some dependence upon the AR and respond, at least transiently, to androgen ablation therapy. However, the relationship between endogenous androgen levels and cancer etiology is unclear. High levels of androgens have traditionally been viewed as driving abnormal proliferation leading to cancer, but it has also been suggested that low levels of androgen could induce selective pressure for abnormal cells. We formulate a mathematical model of androgen regulated prostate growth to study the effects of abnormal androgen levels on selection for pre-malignant phenotypes in early prostate cancer development.     

Physiological responses to folate overproduction in <Emphasis Type="Italic">Lactobacillus plantarum</Emphasis> WCFS1

Background  

Using a functional genomics approach we addressed the impact of folate overproduction on metabolite formation and gene expression in Lactobacillus plantarum WCFS1. We focused specifically on the mechanism that reduces growth rates in folate-overproducing cells.     

Transcriptional profiling of inductive mesenchyme to identify molecules involved in prostate development and disease

Background  

The mesenchymal compartment plays a key role in organogenesis, and cells within the mesenchyme/stroma are a source of potent molecules that control epithelia during development and tumorigenesis. We used serial analysis of gene expression (SAGE) to profile a key subset of prostatic mesenchyme that regulates prostate development and is enriched for growth-regulatory molecules.     

Daily variation and effect of dietary folate on urinary pteridines

Introduction

Urinary pteridines are putative molecular biomarkers for noninvasive cancer screening and prognostication. Central to their translational biomarker development is the need to understand the sources and extent of their non-epidemiological variation.

Objectives

This study was designed to characterize the two primary sources of urinary pteridine variance: daily variation and the effect of dietary folate.

Methods

Daily variation was studied by collecting urine specimens (n = 81) three times daily for 3 days. The effect of dietary folate was investigated in a treatment study in which urine specimens (n = 168) were collected daily during a control week and a treatment week during which participants received dietary folate supplements. Measurements of six urinary pteridines were made using high-performance liquid chromatography–tandem mass spectrometry. Coefficients of variation were calculated to characterize daily variance between and within subjects, while nearest neighbor non-parametric analyses were used to identify diurnal patterns and measure dietary folate effects.

Results

Daily variance was approximately 35 % RSD for both within-day and between-day periods for most pteridines. Diurnal patterns in response to circadian rhythms were similarly observed for urinary pteridines. Folate supplementation was shown to alter urinary pteridine profiles in a pathway dependent manner, suggesting that dietary folate may regulate endogenous neopterin and biopterin biosynthesis.

Conclusions

Urinary pteridine levels were found to be responsive to both daily variation and folate supplementation. These findings provide new insights into pteridine biosynthesis and regulation as well as useful information for the design of future clinical translational research.

     

Decreased intracellular zinc in human tumorigenic prostate epithelial cells: a possible role in prostate cancer progression

Background  

Zinc plays important roles in maintaining normal function of the prostate and in development of prostate malignancy. It has been demonstrated that prostate malignant epithelial cells contain much less cellular zinc than the surrounding normal epithelial cells. However, the pathway(s) which leads to lower zinc accumulation in malignant prostate epithelial cells is poorly understood. In this study, the zinc homeostatic features of two human prostate epithelial cell lines (non-tumorigenic, RWPE1, and tumorigenic, RWPE2) were investigated. Effects of over-expression of ZIP1 in RWPE2 on cell proliferation and apoptosis were also studied.     

Optimization of laser capture microdissection and RNA amplification for gene expression profiling of prostate cancer

Background  

To discover prostate cancer biomarkers, we profiled gene expression in benign and malignant cells laser capture microdissected (LCM) from prostate tissues and metastatic prostatic adenocarcinomas. Here we present methods developed, optimized, and validated to obtain high quality gene expression data.     

Androgen receptor expression in the rat prostate is down-regulated by dietary phytoestrogens

Background  

It is well established that the growth of the prostate gland is a hormone-dependent phenomenon involving both androgenic and estrogenic control. Proliferation of prostate cells is, at least in part, under control of estrogen receptor beta (ER-beta). Phytoestrogens bind ER-beta with high affinity and therefore may have antiproliferative effects in the prostate.     

Androgen receptor signaling is required for androgen-sensitive human prostate cancer cell proliferation and survival

Background  

Androgens and androgen receptors (AR) regulate normal prostate development and growth. They also are involved in pathological development of prostatic diseases, including benign prostatic hyperplasia (BPH) and prostate cancer (PCa). Antiandrogen therapy for PCa, in conjunction with chemical or surgical castration, offers initial positive responses and leads to massive prostate cell death. However, cancer cells later appear as androgen-independent PCa. To investigate the role of AR in prostate cell proliferation and survival, we introduced a vector-based small interfering RNA (siRNA). This siRNA targeted 5'-untranslated region of AR mRNA for extended suppression of AR expression in androgen-sensitive human prostate LNCaP cells.     

INTS6/DICE1 inhibits growth of human androgen-independent prostate cancer cells by altering the cell cycle profile and Wnt signaling

Background  

The gene encoding integrator complex subunit 6 (INTS6), previously known as deleted in cancer cells 1 (DICE1, OMIM 604331) was found to be frequently affected by allelic deletion and promoter hypermethylation in prostate cancer specimens and cell lines. A missense mutation has been detected in prostate cancer cell line LNCaP. Together, these results suggest INTS6/DICE1 as a putative tumor suppressor gene in prostate cancer. In this study, we examined the growth inhibitory effects of INTS6/DICE1 on prostate cancer cells.     

Genetic Polymorphisms of the Glycine N-Methyltransferase and Prostate Cancer Risk in the Health Professionals Follow-Up Study

Purpose

Glycine N-methyltransferase (GNMT) affects genetic stability by regulating the ratio of S-adenosylmethionine to S-adenosylhomocysteine, by binding to folate, and by interacting with environmental carcinogens. In Taiwanese men, GNMT was found to be a tumor susceptibility gene for prostate cancer. However, the association of GNMT with prostate cancer risk in other ethnicities has not been studied. It was recently reported that sarcosine, which is regulated by GNMT, increased markedly in metastatic prostate cancer. We hereby explored the association of GNMT polymorphisms with prostate cancer risk in individuals of European descent from the Health Professionals Follow-up Study (HPFS).

Methods

A total of 661 incident prostate cancer cases and 656 controls were identified from HPFS. The GNMT short tandem repeat polymorphism 1 (STRP1), 4-bp insertion/deletion polymorphisms (INS/DEL) and the single nucleotide polymorphism rs10948059 were genotyped to test for their association with prostate cancer risk.

Results

The rs10948059 T/T genotype was associated with a 1.62-fold increase in prostate cancer risk (95% confidence interval (CI): 1.18, 2.22) when compared with the C/C genotype. The STRP1 ≥16GAs/≥16GAs genotype was associated with decreased risk of prostate cancer when compared with the <16GAs/<16GAs genotype (odds ratio (OR) = 0.68; 95% CI: 0.46, 1.01). INS/DEL was not associated with prostate cancer risk. Haplotypes containing the rs10948059 T allele were significantly associated with increased prostate cancer risk.

Conclusion

In men of European descent, the GNMT rs10948059 and STRP1 were associated with prostate cancer risk. Compared to the study conducted in Taiwanese men, the susceptibility GNMT alleles for prostate cancer had a reverse relationship. This study highlights the differences in allelic frequencies and prostate cancer susceptibility in different ethnicities.     

In silico experimentation with a model of hepatic mitochondrial folate metabolism

Background  

In eukaryotes, folate metabolism is compartmentalized and occurs in both the cytosol and the mitochondria. The function of this compartmentalization and the great changes that occur in the mitochondrial compartment during embryonic development and in rapidly growing cancer cells are gradually becoming understood, though many aspects remain puzzling and controversial.     

Equol an isoflavonoid: potential for improved prostate health, <Emphasis Type="Italic">in vitro</Emphasis> and <Emphasis Type="Italic">in vivo</Emphasis>evidence

Background  

To determine: in vitro binding affinity of equol for 5alpha-dihydrotestosterone (5alpha-DHT), in vitro effects of equol treatment in human prostate cancer (LNCap) cells, and in vivo effects of equol on rat prostate weight and circulating levels of sex steroid hormones.     

Knockout of the folate transporter <Emphasis Type="Italic">folt-1</Emphasis> causes germline and somatic defects in <Emphasis Type="Italic">C. elegans</Emphasis>

Background  

The C. elegans gene folt-1 is an ortholog of the human reduced folate carrier gene. The FOLT-1 protein has been shown to transport folate and to be involved in uptake of exogenous folate by worms. A knockout mutation of the gene, folt-1(ok1460), was shown to cause sterility, and here we investigate the source of the sterility and the effect of the folt-1 knockout on somatic function.     

<Emphasis Type="Italic">Propionibacterium acnes</Emphasis> infection induces upregulation of inflammatory genes and cytokine secretion in prostate epithelial cells

Background  

The immune stimulating bacterium Propionibacterium acnes is a frequent colonizer of benign and malignant prostate tissue. To understand the pathogenesis of the earliest phase of this infection, we examined the P. acnes triggered immune response in cultivated prostate epithelial cells.     

A combined approach to data mining of textual and structured data to identify cancer-related targets

Background  

We present an effective, rapid, systematic data mining approach for identifying genes or proteins related to a particular interest. A selected combination of programs exploring PubMed abstracts, universal gene/protein databases (UniProt, InterPro, NCBI Entrez), and state-of-the-art pathway knowledge bases (LSGraph and Ingenuity Pathway Analysis) was assembled to distinguish enzymes with hydrolytic activities that are expressed in the extracellular space of cancer cells. Proteins were identified with respect to six types of cancer occurring in the prostate, breast, lung, colon, ovary, and pancreas.