Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nitric oxide ((.)NO) induces apoptosis at high concentrations by S-nitrosating proteins such as glyceraldehyde-3-phosphate dehydrogenase. This literature analysis revealed that failure to sustain high (.)NO concentrations is common to all cancers. In cervical, gastric, colorectal, breast, and lung cancer, the cause of this failure is the inadequate expression of inducible nitric oxide synthase (iNOS), resulting from the inhibition of iNOS expression by TGF-beta1 at the mRNA level. In bladder, renal, and prostate cancer, the reason for the insufficient (.)NO levels is the depletion of arginine, resulting from arginase overexpression. Arginase competes with iNOS for arginine, catalyzing its hydrolysis to ornithine and urea. In gliomas and ovarian sarcomas, low (.)NO levels are caused by inhibition of iNOS by N-chlorotaurine, produced by infiltrating neutrophils. Stimulated neutrophils express myeloperoxidase, catalyzing H2O2 oxidation of Cl- to HOCl, which N-chlorinates taurine at its concentration of 19 mM in neutrophils. In squamous cell carcinomas of the skin, ovarian cancers, lymphomas, Hodgkin's disease, and breast cancers, low (.)NO concentrations arise from the inhibition of iNOS by N-bromotaurine, produced by eosinophil-peroxidase-expressing infiltrating eosinophils. Eosinophil peroxidase catalyzes the H2O2 oxidation of Br- to HOBr, which N-brominates taurine to N-bromotaurine at its concentration of 15 mM in eosinophils. In microvascularized tumors, the (.)NO concentration is further depleted; (.)NO is rapidly consumed by red blood cells (RBCs) through S-nitrosation of RBC glutathione and hemoglobin, and by oxidation to nitrate by RBC oxyhemoglobin. Angiogenesis-inhibiting antibodies are currently used to treat cancers; their mode of action is not, as previously thought, reduction of the tumor O2 or nutrient supply. They actually decrease the loss of (.)NO to RBCs.
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PMID:Apoptosis-inducing high (.)NO concentrations are not sustained either in nascent or in developed cancers. 1875 45

We report here that the polycomb group protein Bmi1 promotes prostate tumorigenesis. Bmi1 is detected at higher levels in androgen-independent PC3 and DU145 than in androgen-dependent LNCaP prostate cancer (CaP) cells. Ectopic Bmi1 enhanced the expression of human telomerase reverse transcriptase (hTERT) and suppressed the exression of p16(INK4A) and p14(ARF) in CaP cells. Consistent with these observations, immunohistochemical staining of 51 cases of primary CaP specimens revealed 1.4 fold (p=0.014) and 1.3 fold (p=0.051) higher levels of Bmi1-positive cells in carcinoma compared to normal prostatic epithelial cells and PIN, respectively. In primary CaPs, Bmi1 expression was associated with a reduction in p16(INK4A) and p14(ARF). Furthermore, in comparison to empty vector-transfected cells, Bmi1-expressing DU145 cells formed significantly larger tumors in NOD/SCID mice. Taken together, we demonstrate that Bmi1 promotes prostate tumorigenesis.
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PMID:Bmi1 promotes prostate tumorigenesis via inhibiting p16(INK4A) and p14(ARF) expression. 1881 67

Urea-based, low molecular weight ligands of glutamate carboxypeptidase II (GCPII) have demonstrated efficacy in various models of neurological disorders and can serve as imaging agents for prostate cancer. To enhance further development of such compounds, we determined X-ray structures of four complexes between human GCPII and urea-based inhibitors at high resolution. All ligands demonstrate an invariant glutarate moiety within the S1' pocket of the enzyme. The ureido linkage between P1 and P1' inhibitor sites interacts with the active-site Zn(1)(2+) ion and the side chains of Tyr552 and His553. Interactions within the S1 pocket are defined primarily by a network of hydrogen bonds between the P1 carboxylate group of the inhibitors and the side chains of Arg534, Arg536, and Asn519. Importantly, we have identified a hydrophobic pocket accessory to the S1 site that can be exploited for structure-based design of novel GCPII inhibitors with increased lipophilicity.
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PMID:Interactions between human glutamate carboxypeptidase II and urea-based inhibitors: structural characterization. 1905 59

Prostate specific membrane antigen (PSMA) is a validated molecular marker for prostate cancer. A series of glutamate-urea (Glu-urea-X) heterodimeric inhibitors of PSMA were designed and synthesized where X = epsilon-N-(o-I, m-I, p-I, p-Br, o-Cl, m-Cl, p-Cl, p-F, H)-benzyl-Lys and epsilon-(p-I, p-Br, p-Cl, p-F, H)-phenylureido-Lys. The affinities for PSMA were determined by screening in a competitive binding assay. PSMA binding of the benzyllysine series was significantly affected by the nature of the halogen substituent (IC(50) values, Cl < I = Br << F = H) and the ring position of the halogen atom (IC(50) values, p-I < o-I << m-I). The halogen atom had little affect on the binding affinity in the para substituted phenylureido-Lys series. Two lead iodine compounds were radiolabeled with (123)I and (131)I and demonstrated specific PSMA binding on human prostate cancer cells, warranting evaluation as radioligands for the detection, staging, and monitoring of prostate cancer.
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PMID:A series of halogenated heterodimeric inhibitors of prostate specific membrane antigen (PSMA) as radiolabeled probes for targeting prostate cancer. 1911 Oct 54

We have discovered several tubulin-active compounds in our previous studies. In the establishment of a compound library of small molecule weight tubulin ligands, 14 new N-3-haloacylaminophenyl-N'-(alkyl/aryl) urea analogs were designed and synthesized. The structure-activity relationship (SAR) analysis revealed that (i) the order of anticancer potency for the 3-haloacylamino chain was following -CH(2)Br>-CHBrCH(3); (ii) the N'-substituent moiety was not essential for the anticancer activity, and a proper alkyl substitution might enhance the anticancer activity. Among these analogs, the compounds 16j bearing bromoacetyl at the N'-end exhibited a potent activity against eight human tumor cell lines, including CEM (leukemia), Daudi (lymphoma), MCF-7 (breast cancer), Bel-7402 (hepatoma), DU-145 (prostate cancer), DND-1A (melanoma), LOVO (colon cancer) and MIA Paca (pancreatic cancer), with the IC(50) values between 0.38 and 4.07 microM. Interestingly, compound 16j killed cancer cells with a mechanism independent of the tubulin-based mechanism, indicating a significant change of the action mode after the structure modification.
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PMID:Synthesis and activity evaluation of phenylurea derivatives as potent antitumor agents. 1941 Apr 66

Analysis of methylated DNA, which refers to 5-methycytosine (5mC) versus cytosine (C) at specific loci in genomic DNA (gDNA), has received increased attention in epigenomics, particularly in the area of cancer biomarkers. Many different methods for analysis of methylated DNA rely on initial reaction of gDNA with concentrated acidic sodium bisulfite to quantitatively convert C to uracil (U) via sulfonation of denatured, single-stranded gDNA under conditions where 5mC is resistant to analogous sulfonation leading to thymine (T). These methods typically employ polymerase chain reaction (PCR) amplification after bisulfite conversion, thereby leading to readily detectable amounts of amplicons where T and C are measured as surrogates for C and 5mC in the original unconverted gDNA. However, incomplete bisulfite conversion of C in gDNA has been reported to be a common source of error in analysis of methylated DNA. Incomplete conversion can be revealed during the course of bisulfite sequencing, which is the generally accepted "gold standard" for analysis of methylated DNA. Previous bisulfite sequencing investigations of conventional predenaturation of gDNA with NaOH followed by the use of bisulfite containing added urea to maintain denaturation and thus mitigate incomplete conversion of C have been reported to give conflicting results. The current study describes a new approach where conventional predenaturation of gDNA with NaOH is instead achieved with formamide and maintains denaturation during subsequent sample handling and sulfonation. This formamide-based method was applied to 46 formalin-fixed/paraffin-embedded (FFPE) biopsy tissue specimens from well-characterized patients with primary prostate cancer. These specimens were representative of difficult-to-analyze samples due to the chemically compromised nature of the gDNA, which was recovered by modifying the protocol for a commercially available total RNA/DNA extraction kit (RecoverALL). An additional novel aspect of this study was analysis of CpG-rich promoter regions of two prostate cancer-related genes: glutathione S-transferase pi (GSTPi) and retinoic acid receptor beta2 (RARbeta2). High-quality bisulfite sequencing results were obtained for both genes in 43 of 46 (93%) specimens. Detection of methylated GSTPi and RARbeta2 genes was significantly associated with primary prostate cancer as compared with the benign prostate (Fisher's exact test, P < 0.001). The sensitivity and specificity of detection of methylated GSTPi and RARbeta2 genes were 86% and 100% and 91% and 100%, respectively. Moreover, the presence of either methylated gene was detected in primary prostate cancer with sensitivity and specificity of 100% and 100%, respectively. The results demonstrated a high degree of reliability of formamide-based denaturation and bisulfite conversion that should extend, generally, to FFPE and other types of samples intended for any analytical method predicated on bisulfite conversion. This pilot study also demonstrated the efficacy of determining methylation of these two genes with high sensitivity and specificity in FFPE biopsy tissue specimens. Moreover, the results showed a highly significant association of methylated GSTPi and RARbeta2 genes with primary prostate cancer. Finally, this improved procedure for determining these two methylated genes may allow the detection of prostate cancer cells in core biopsy specimens with insufficient numbers of cells and poor morphology.
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PMID:Formamide as a denaturant for bisulfite conversion of genomic DNA: Bisulfite sequencing of the GSTPi and RARbeta2 genes of 43 formalin-fixed paraffin-embedded prostate cancer specimens. 1950 31

One reported function of the tumor suppressor p19(Arf) is to stabilize p53, providing a critical checkpoint in the response to oncogenic insults. Acute loss of Pten leads to an increase in the abundance of p19(Arf), p53, and p21 proteins as part of a fail-safe senescence response. Here, we report that loss of p19(Arf) in prostate epithelium does not accelerate-but rather partially inhibits-the prostate cancer phenotype of Pten-deficient mice. Moreover, cellular senescence and a further decrease in the number of pre-neoplastic glands were observed in prostates of the Pten-p19(Arf) double-mutant mice. In both prostate epithelium and primary mouse embryo fibroblasts (MEFs), the increase in p53 protein abundance found upon loss of Pten was unaffected by the simultaneous loss of p19(Arf). However, in contrast to that in the prostate epithelium, p19(Arf) deficiency in MEFs lacking Pten abolished cell senescence and promoted hyperproliferation and transformation despite the unabated increase in p53 abundance. Consistent with the effect of p19(Arf) loss in Pten-deficient mouse prostate, we found that in human prostate cancers, loss of PTEN was not associated with loss of p14(ARF) (the human equivalent of mouse p19(Arf)). Collectively, these data reveal differential consequences of p19(Arf) inactivation in prostate cancer and MEFs upon Pten loss that are independent of the p53 pathway.
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PMID:Differential p53-independent outcomes of p19(Arf) loss in oncogenesis. 1969 Mar 30

Illudin S and M (1, 2) are highly toxic sesquiterpenes found in the basidiomycete Omphalotus illudens. Illudins have a low therapeutic index, but acylfulvene derivatives display potent in vivo antitumor activity against a variety of multidrug resistant tumors. The lead acylfulvene (4), irofulven (5), in a randomized phase IIB clinical trial significantly increased overall survival in patients with metastatic hormone-refractory prostate cancer who failed prior treatment with two different standard chemotherapeutic regimens. Irofulven is unique, as the primary allylic hydroxyl group can undergo displacement with a variety of nucleophiles to produce analogues that retain key functional groups required for biological activity including the reactive cyclopropylmethyl carbinol and alpha,beta-unsaturated ketone. As described here, we synthesized a variety of urea, carbamate, and sulfonamide derivatives that retain key functional groups and display potent biological activity toward target solid tumor cells in vitro but are relatively nontoxic toward a nontarget B-cell derived cell line.
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PMID:Structure-activity studies of urea, carbamate, and sulfonamide derivatives of acylfulvene. 2006 64

MicroRNAs (miRNA) regulate complex patterns of gene expression, and the relevance of altered miRNA expression to ovarian cancer remains to be elucidated. By comprehensively profiling expression of miRNAs and mRNAs in serous ovarian tumors and cell lines and normal ovarian surface epithelium, we identified hundreds of potential miRNA-mRNA targeting associations underlying cancer. Functional overexpression of miR-31, the most underexpressed miRNA in serous ovarian cancer, repressed predicted miR-31 gene targets including the cell cycle regulator E2F2. MIR31 and CDKN2A, which encode p14(ARF) and p16(INK4A), are located at 9p21.3, a genomic region commonly deleted in ovarian and other cancers. p14(ARF) promotes p53 activity, and E2F2 overexpression in p53 wild-type cells normally leads via p14(ARF) to an induction of p53-dependent apoptosis. In a number of serous cancer cell lines with a dysfunctional p53 pathway (i.e., OVCAR8, OVCA433, and SKOV3), miR-31 overexpression inhibited proliferation and induced apoptosis; however, in other lines (i.e., HEY and OVSAYO) with functional p53, miR-31 had no effect. Additionally, the osteosarcoma cell line U2OS and the prostate cancer cell line PC3 (p14(ARF)-deficient and p53-deficient, respectively) were also sensitive to miR-31. Furthermore, miR-31 overexpression induced a global gene expression pattern in OVCAR8 associated with better prognosis in tumors from patients with advanced stage serous ovarian cancer, potentially affecting many genes underlying disease progression. Our findings reveal that loss of miR-31 is associated with defects in the p53 pathway and functions in serous ovarian cancer and other cancers, suggesting that patients with cancers deficient in p53 activity might benefit from therapeutic delivery of miR-31.
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PMID:Molecular profiling uncovers a p53-associated role for microRNA-31 in inhibiting the proliferation of serous ovarian carcinomas and other cancers. 2017 98

Expression of the INK4b/ARF/INK4a tumor suppressor locus in normal and cancerous cell growth is controlled by methylation of histone H3 at lysine 27 (H3K27me) as directed by the Polycomb group proteins. The antisense noncoding RNA ANRIL of the INK4b/ARF/INK4a locus is also important for expression of the protein-coding genes in cis, but its mechanism has remained elusive. Here we report that chromobox 7 (CBX7) within the polycomb repressive complex 1 binds to ANRIL, and both CBX7 and ANRIL are found at elevated levels in prostate cancer tissues. In concert with H3K27me recognition, binding to RNA contributes to CBX7 function, and disruption of either interaction impacts the ability of CBX7 to repress the INK4b/ARF/INK4a locus and control senescence. Structure-guided analysis reveals the molecular interplay between noncoding RNA and H3K27me as mediated by the conserved chromodomain. Our study suggests a mechanism by which noncoding RNA participates directly in epigenetic transcriptional repression.
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PMID:Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by polycomb CBX7 in transcriptional silencing of INK4a. 2054 99


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