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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic inflammation can augment tumor development in various types of cancers, including prostate cancer (PCa). Reduction of inflammation is therefore an important anticancer therapeutic opportunity. Here, we report four anti-proliferative phytocompounds in Wedelia chinensis, an oriental herbal medicine, identified through their ability to modulate the androgen receptor (AR) activation of transcription from prostate-specific antigen promoter in PCa cells. The 50% inhibition concentration values of indole-3-carboxylaldehyde, wedelolactone, luteolin and apigenin, were 34.9, 0.2, 2.4 and 9.8 muM, respectively. A formula that combined the phytocompounds in the same proportions as in the herbal extract decreased the dosage of each compound required to achieve maximal AR inhibition. In correlation with the AR suppression effect, these active compounds specifically inhibited the growth of AR-dependent PCa cells and as a combination formula they also synergistically suppressed growth in AR-dependent PCa cells. Our study has identified synergistic effects of active compounds in W. chinensis and demonstrated their potential in PCa prevention and therapy. The paradigm of multiple activities and synergism is a useful framework to investigate the therapeutic effects of whole extracts from assorted medicinal plant species.
Carcinogenesis 2007 Dec
PMID:Compounds from Wedelia chinensis synergistically suppress androgen activity and growth in prostate cancer cells. 1794 63

Prostate cancer is a leading solid tumor among men in the Western world. Androgens play an important role in the carcinogenesis and treatment of prostate cancer. CYP3A5 is a cytochrome P450 superfamily member which also has activity in testosterone metabolism. In this study, we looked for two-gene interactions associated with clinical characteristics of prostate cancer in the Finnish population. We used multifactor-dimensionality reduction for the identification of the two-gene interactions in androgen metabolism pathway genes together with clinical characteristics of prostate cancer among 754 genotyped prostate cancer patients. The CYP3A5*3/*3 and SRD5A2 A49T GG genotype interaction was associated with the clinical tumor stage T2-T4 (T-stage, TNM classification) with odds ratio (OR) 2.14, 95% confidence interval (CI) 1.35-3.40. Patients with CYP3A5*3/*3 and KLK3 I179T CC/TC genotypes had increased OR 2.30, 95% CI 1.16-4.58 for metastatic disease. Further, two-gene interaction CYP3A5*3/*3 and KLK3 -252A > G AA was associated with Gleason scores >or=7 with OR 1.52, 95% CI 1.11-2.09. Prostate cancer patients with CYP3A5*3/*3 and KLK -252A > G GG/AG genotypes had decreased OR of 0.70 with 95% CI 0.50-0.98 for high prostate-specific antigen levels at diagnosis. For prostate cancer patients aged below 65 years, the OR for interaction of CYP3A5*1/*3 or *1/*1 and AKR1C3 Q5H CC genotypes was 1.84 with 95% CI 1.03-3.28. For prostate cancer, the best two-gene interaction included genotypes SRD5A2 V89L GG and AKR1C3 Q5H CC with OR 1.30, 95% CI 1.01-1.66. It remains to be clarified whether these polymorphism associations identified here are also present in other populations.
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PMID:The interaction of CYP3A5 polymorphisms along the androgen metabolism pathway in prostate cancer. 1830 54

The function of the androgen-regulated homeobox protein NKX3.1 in prostate cancer is controversial. NKX3.1 is necessary for correct prostate development and undergoes frequent allelic loss in prostate cancer. However, no mutations occur in the coding region and some particularly aggressive cancers over-express the protein. Nevertheless NKX3.1 is often referred to as candidate tumor suppressor gene. Recent findings suggest a function in protection against oxidative damage involved in prostate carcinogenesis. Thus NKX3.1 may act differently at various stages of prostate cancer. Unlike a classical tumor suppressor NKX3.1 is up-regulated by androgens and down-regulated by phytoestrogens. In this study we performed RNAi based functional analysis by knocking down NKX3.1 expression in LNCaP prostate cancer cells and analyzing the impact of NKX3.1 on gene expression and cell proliferation. Knock-down of NKX3.1 evoked a massive down-regulation of NKX3.1 expression, followed by reduction in mRNA expression of the androdrogen receptor (AR) and the insulin-like growth factor receptor (IGF-1R). Western blot analysis showed strong decreases of NKX3.1, AR, and IGF-1R protein expression. Concomitantly, cell proliferation decreased and expression of prostate-specific antigen (PSA) mRNA and its secretion were diminished, whereas expression of IGF binding protein 3 (IGFBP-3) and MMP tissue inhibitor 3 (TIMP-3) was up-regulated. In tumor cells not deprived of NKX3.1 expression this gene still has a function which might differ from its role in prostate development and carcinogenesis. NKX3.1 knock-down altered the expression of genes highly relevant in prostate cancer cell proliferation and apoptosis. In LNCaP NKX3.1 most probably plays the role of an androgen-regulated transcription factor whose down-regulation is paralleled by anti-proliferative and pro-apoptotic effects. Since NKX3.1 can regulate AR expression it may become a target for interference in hormone refractory prostate carcinoma.
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PMID:Functional analysis of NKX3.1 in LNCaP prostate cancer cells by RNA interference. 1836 Jul 15

Two non-synonymous single-nucleotide polymorphisms (SNPs), Ser217Leu and Ala541Thr, in the elaC homolog 2 (Escherichia coli) (ELAC2) gene have been related to prostate cancer risk in previous studies, though with inconsistent results. The association of ELAC2 haplotypes with prostate cancer risk has not yet been explored. We assessed whether sequence variants in ELAC2 were associated with the risk of total or aggressive prostate cancer. In a nested case-control design within the Health Professionals Follow-Up Study, we identified 659 participants with prostate cancer diagnosed after they provided a blood specimen in 1993 and before January 2000. Controls were 656 age-matched men without prostate cancer who had had a prostate-specific antigen test after providing a blood specimen. We genotyped eight tagging SNPs in ELAC2 to test for the association between sequence variances in ELAC2 and prostate cancer. No individual SNP (including Ser217Leu) was associated with the risk of prostate cancer. Ala541Thr is a rare SNP in this population. One common haplotype (hap4) was statistically significantly associated with an increased risk of prostate cancer [odds ratio (OR) = 1.39, 95% confidence interval = 1.05-1.85]. Two common promoter SNPs and three common haplotypes were statistically significantly associated with aggressive prostate cancer (carriers versus non-carriers-snp2: OR = 1.43, snp3: OR = 0.69, hap1: OR = 1.47, hap2: OR = 0.72, hap4: OR = 1.51; global P-value for all common haplotypes = 0.11). Common SNPs and haplotypes of ELAC2 were associated with risk of aggressive prostate cancer.
Carcinogenesis 2008 May
PMID:Sequence variants of elaC homolog 2 (Escherichia coli) (ELAC2) gene and susceptibility to prostate cancer in the Health Professionals Follow-Up Study. 1837 59

Androgen antagonists or androgen deprivation are the primary therapeutic modalities for the treatment of prostate cancer. Invariably, however, the disease becomes progressive and unresponsive to androgen ablation therapy (hormone refractory). The molecular mechanisms by which androgen antagonists inhibit prostate cancer proliferation are not fully defined. In this study, we identify two molecules which are required for effective prostate cancer cell responsiveness to androgen antagonists. We establish that androgen receptor (AR)-dependent transcriptional suppression by androgen antagonists requires the tumor suppressor prohibitin. This requirement for prohibitin was demonstrated using structurally-distinct androgen antagonists, stable and transient knockdown of prohibitin and transfected and endogenous AR-responsive genes. The SWI-SNF complex core ATPase BRG1, but not its closely-related counterpart ATPase BRM, is required for this repressive action of prohibitin on AR-responsive promoters. Androgen antagonists induce recruitment of prohibitin and BRG1 to endogenous AR-responsive promoters and induce a physical association between AR and prohibitin and BRG1. The recruitment of prohibitin to endogenous AR-responsive promoters is dependent upon antagonist-bound AR. Prohibitin binding in the prostate-specific antigen (PSA) promoter results in the recruitment of BRG1 and the dissociation of p300 from the PSA promoter. These findings suggest that prohibitin may function through BRG1-mediated local chromatin remodeling activity and the removal of p300-mediated acetylation to produce androgen antagonist-mediated transcriptional repression. Furthermore, in addition to its necessary role in AR-mediated transcriptional repression, we demonstrate that prohibitin is required for full and efficient androgen antagonist-mediated growth suppression of prostate cancer cells.
Carcinogenesis 2008 Sep
PMID:Prohibitin and the SWI/SNF ATPase subunit BRG1 are required for effective androgen antagonist-mediated transcriptional repression of androgen receptor-regulated genes. 1848 22

The aim of our study was to assess the importance of the CXC chemokine and interleukin (IL)-8 in promoting the transition of prostate cancer (CaP) to the androgen-independent state. Stimulation of the androgen-dependent cell lines, LNCaP and 22Rv1, with exogenous recombinant human interleukin-8 (rh-IL-8) increased androgen receptor (AR) gene expression at the messenger RNA (mRNA) and protein level, assessed by quantitative polymerase chain reaction and immunoblotting, respectively. Using an androgen response element-luciferase construct, we demonstrated that rh-IL-8 treatment also resulted in increased AR transcriptional activity in both these cell lines, and a subsequent upregulation of prostate-specific antigen and cyclin-dependent kinase 2 mRNA transcript levels in LNCaP cells. Blockade of CXC chemokine receptor-2 signaling using a small molecule antagonist (AZ10397767) attenuated the IL-8-induced increases in AR expression and transcriptional activity. Furthermore, in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, coadministration of AZ10397767 reduced the viability of LNCaP and 22Rv1 cells exposed to bicalutamide. Our data show that IL-8 signaling increases AR expression and promotes ligand-independent activation of this receptor in two androgen-dependent cell lines, describing two mechanisms by which this chemokine may assist in promoting the transition of CaP to the androgen-independent state. In addition, our data show that IL-8-promoted regulation of the AR attenuates the effectiveness of the AR antagonist bicalutamide in reducing CaP cell viability.
Carcinogenesis 2008 Jun
PMID:Interleukin-8 signaling promotes androgen-independent proliferation of prostate cancer cells via induction of androgen receptor expression and activation. 1848 23

Chondroitin sulfate is a structurally diverse glycosaminoglycan, which contains a variable degree of sulfation that helps to determine its biological function. It is involved in the regulation of cellular activity and has been implicated in carcinogenesis. To determine if the non-sulfated chondroitin backbone has a functional role in prostate cancer, we analyzed its expression by immunohistochemistry using the 1B5 monoclonal antibody and a set of tissue microarrays constructed with 227 prostate specimen cores from 81 cases of benign prostate tissue and 77 cases of prostate cancer, of which 69 of these cases are matched. Non-sulfated chondroitin was found in the secretory epithelial cells and stromal regions of both prostatic adenocarcinoma and benign prostatic tissues, as well as in the basal cells of benign glands. A higher percentage of cancerous cells were stained positively for non-sulfated chondroitin as compared with benign secretory cells of the same patient. Cancerous cells stained more intensely for non-sulfated chondroitin. This increase in percentage of cells stained and increase in staining intensity were associated with higher pathological T stage and extraprostatic extension. Non-sulfated chondroitin expression (either staining intensity or percentage of cells stained) in adenocarcinoma and its peritumoral stroma correlated significantly with several clinicopathological parameters of unfavorable outcome, including higher pathological T stage and Gleason score, presence of tumor in both prostatic lobes, extraprostatic extension, seminal vesicle involvement and preoperative prostate-specific antigen levels. These data suggest that non-sulfated chondroitin is a potentially useful biomarker for prostate cancer, and may be involved in regulating prostate cancer behavior.
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PMID:Increased expression of non-sulfated chondroitin correlates with adverse clinicopathological parameters in prostate cancer. 1848 97

p66Shc is shown to negatively regulate the life span in mice through reactive oxygen species (ROS) production. Recent reports, however, revealed that p66Shc protein level is significantly elevated in several human cancer tissues and growth-stimulated carcinoma cells, suggesting a mitogenic and carcinogenic role for p66Shc. In this communication, we demonstrate for the first time that p66Shc mediates androgenic growth signals in androgen-sensitive human prostate cancer cells through mitochondrial ROS production. Growth stimulation of prostate cancer cells with 5alpha-dihydrotestosterone (DHT) is accompanied by increased p66Shc level and ROS production, which is abolished by antioxidant treatments. However, antioxidant treatments do not affect the transcriptional activity of androgen receptor (AR) as observed by its inability to block DHT-induced prostate-specific antigen expression, an AR-dependent correlate of prostate cancer progression. Elevated expression of p66Shc by cDNA transfection increases the basal cell proliferation and, thus, reduces additional DHT-induced cell proliferation. Furthermore, DHT increases the translocation of p66Shc into mitochondria and its interaction with cytochrome c. Conversely, both redox-negative p66Shc mutant (W134F), which is deficient in cytochrome c interaction, and p66Shc small interfering RNA decrease DHT-induced cell proliferation. These results collectively reveal a novel role for p66Shc-ROS pathway in androgen-induced prostate cancer cell proliferation and, thus, may play a role in early prostate carcinogenesis.
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PMID:Mitochondrial redox signaling by p66Shc is involved in regulating androgenic growth stimulation of human prostate cancer cells. 1850 39

The introduction of total prostate-specific antigen (tPSA) testing in serum has revolutionized the detection and management of men with prostate cancer. This review will highlight some of the exciting new developments in the field of prostate cancer screening in general and from our SPORE research program at Memorial-Sloan Kettering Cancer Center. First, it is important to understand that the inherent variability of tPSA levels affects the interpretation of any single results. Total variation in tPSA includes both analytical (i.e., pre-analytical sample handling, laboratory processing, assay performance, and standardization) and biological variation (i.e., metabolism, renal elimination, medication, physical and sexual activity, size and integrity of the prostate). Second, recent evidence demonstrates that no single tPSA cut-off separates men at high risk for prostate cancer from men at low risk or men with "significant" (high grade, high volume) cancer from those with low grade, indolent cancer. Taken together with a man's age, family history, ethnicity, and digital rectal exam results, tPSA levels add to the overall estimate of the risk of cancer, allowing men to share in the decision about a biopsy. Third, men who will eventually develop prostate cancer have increased tPSA levels years or decades before the cancer is diagnosed. These tPSA levels may reflect the long duration of prostate carcinogenesis and raise the question about a causal role for tPSA in prostate cancer development and progression. Total prostate-specific antigen measurements before age 50 could help risk stratify men for intensity of prostate cancer screening. Fourth, enhancing the diagnostic accuracy of tPSA, especially its specificity, is of particular importance, since higher specificity translates into fewer biopsies in men not affected by prostate cancer. While tPSA velocity has been shown to improve the specificity of tPSA, its sensitivity is too low to avoid prostate biopsy in a patient with an elevated tPSA level. Moreover, prospective screening studies have reported that tPSA velocity does not add diagnostic value beyond tPSA level. At this time, tPSA velocity appears most useful after diagnosis and after treatment, but its value in screening and prognostication remains to be shown. Finally, while free PSA molecular isoforms and human kallikrein-related peptidase 2 (hK2) hold the promise for detection, staging, prognosis, and monitoring of prostate cancer, evidence from large prospective clinical trials remain to be reported.
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PMID:Screening for prostate cancer: an update. 1904 89

Lupeol, a dietary triterpene, was shown to decrease serum prostate-specific antigen levels and inhibit the tumorigenicity of prostate cancer (CaP) cells in vivo. Here, we show that Lupeol inhibits the proliferative potential of CaP cells and delineated its mechanism of action. Employing a focused microarray of human CaP-associated genes, we found that Lupeol significantly modulates the expression level of genes such as ERBB2, tissue inhibitor of metalloproteinases-3, cyclin D1 and matrix metalloproteinase (MMP)-2 that are known to be associated with proliferation and survival. A common feature of these genes is that all of them are known to either regulate or act as downstream target of beta-catenin signaling that is highly aberrant in CaP patients. Lupeol treatment significantly (1) reduced levels of beta-catenin in the cytoplasmic and nuclear fractions, (2) modulated expression levels of glycogen synthase kinase 3 beta (GSK3beta)-axin complex (regulator of beta-catenin stability), (3) decreased the expression level and enzymatic activity of MMP-2 (downstream target of beta-catenin), (4) reduced the transcriptional activation of T Cell Factor (TCF) responsive element (marker for beta-catenin signaling) in pTK-TCF-Luc-transfected cells and (5) decreased the transcriptional activation of MMP-2 gene in pGL2-MMP-2-Luc-transfected cells. Effects of Lupeol treatment on beta-catenin degradation were significantly reduced in CaP cells where axin is knocked down through small interfering RNA transfection and GSK3beta activity is blocked. Collectively, these data suggest the multitarget efficacy of Lupeol on beta-catenin-signaling network thus resulting in the inhibition CaP cell proliferation. We suggest that Lupeol could be developed as an agent for chemoprevention as well as chemotherapy of human CaP.
Carcinogenesis 2009 May
PMID:Lupeol inhibits proliferation of human prostate cancer cells by targeting beta-catenin signaling. 1923 58


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