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

Our study examined the in vitro and in vivo responses of a newly discovered HGF/SF antagonist, NK4, on HGF/SF-promoted growth of human prostate cancer cells (PC-3). Nude mice were s.c. injected with either PC-3- and/or HGF/SF-producing fibroblasts (MRC5), and tumor size was measured over a 4-week period. rh-HGF/SF and/or NK4 were introduced by osmotic minipumps. An in vitro study found that NK4 significantly suppressed HGF/SF-induced invasion (HGF/SF; p < 0.01 vs. HGF/SF+NK4) and migration (HGF/SF; p < 0.05 vs. HGF/SF+NK4). Similarly, NK4 also suppressed the invasion (MRC5; p < 0.01 vs. MRC5+NK4) and migration (MRC5; p < 0.05 vs. MRC5+NK4) induced by MRC5 cells. NK4 also suppressed HGF/SF- and MRC5-induced tyrosine phosphorylation of the HGF/SF receptor Met as assessed by immunoprecipitation. Using a nude mouse model, prostate tumor volume (mm(3)) was significantly increased in both HGF/SF- (HGF/SF; p < 0.05 vs. control) and MRC5- (MRC5; p < 0.01 vs. control) treated groups compared to the control. In contrast, NK4 alone significantly reduced the growth of prostate tumors (NK4; p < 0.01 vs. control). In addition, NK4 also suppressed both HGF/SF- (HGF/SF; p < 0.01 vs. HGF/SF+NK4) and MRC5- (MRC5; p < 0.05 vs. MRC5+NK4) induced tumor growth in vivo by significantly reducing (p < 0.05) the degree of tumor angiogenesis using a recently discovered family of tumor endothelial markers (TEMs) by Q-RT-PCR analysis. In conclusion, NK4 suppresses both HGF/SF- and MRC5-induced invasion/migration of PC-3 cells in vitro. Furthermore, the HGF/SF antagonist NK4 significantly reduces prostate tumor growth in vivo by inhibiting the degree of tumor angiogenesis as determined by TEM-1 and TEM-8. Finally, our study provides evidence of the therapeutic potential of NK4 in prostate cancer development by antagonising HGF/SF-mediated events.
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PMID:The HGF/SF antagonist NK4 reverses fibroblast- and HGF-induced prostate tumor growth and angiogenesis in vivo. 1284 72

Tumor cells are more sensitive to methionine restriction than normal tissues, a phenomenon known as methionine auxotrophy. Previous studies showed that 5-fluorouracil and methionine restriction act synergistically against a variety of tumors. The purpose of the current studies was to determine the molecular mechanism(s) underlying this synergy. 5-Fluorouracil is known to inhibit thymidylate synthase (TS), a key enzyme that transfers a methyl group from 5,10-methylene-tetrahydrofolate to dUMP during nucleotide biosynthesis. We found that methionine restriction reduced 5,10-methylene-tetrahydrofolate levels by 75% and selectively inhibited TS activity in PC-3 human prostate cancer cells within 24hr, whereas it did not in normal prostate epithelial cells. The observed fall in TS activity was accompanied by a commensurate reduction in TS protein levels as determined by western blot analysis. In contrast, 5-fluorouracil inhibited TS activity by >90% but increased TS protein levels. This increase was abrogated by methionine restriction. Surprisingly, methionine restriction increased 3H-leucine incorporation in PC-3 cells over the first 24hr, suggesting that reduction of TS levels was not simply due to global protein synthesis inhibition. Methionine restriction also significantly reduced the ratio of dUMP to dTTP in PC-3 cells, creating an imbalanced nucleotide pool. These results suggest that synergy between methionine restriction and 5-fluorouracil is attributable to multiple factors, including depletion of reduced folates, selective inhibition of TS, and creation of an imbalanced nucleotide pool. Dietary and/or enzymatic methionine restriction combined with 5-fluoruracil has great promise as a novel treatment for advanced cancer.
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PMID:Methionine restriction selectively targets thymidylate synthase in prostate cancer cells. 1294 60

Metabolic imaging with positron emission tomography (PET) for the staging and monitoring of treatment response has important implications in clinical oncology. The choice of radiotracer is likely to be critically important. The objective of our study was to compare the pharmacokinetics of C-11-methionine with FDG in a group of androgen independent patients with metastatic prostate cancer, to determine the differential metabolism of the two tracers, and to determine the optimal time of imaging after injection in treated and untreated patients. A total of 29 dynamic scans (19 pretreatment and 10 posttreatment) were performed in 10 patients with progressive or new lesions on bone scans (index lesions). A total of 13 index lesions were identified in baseline scans. Patients were infused with 370 MBq C-11-methionine on the couch and 32 dynamic images acquired over 60 minutes. After at least 5 half-lives of C-11, patients were then dynamically imaged (15 frames) for 45 minutes with FDG. Index lesions demonstrated both C-11-methionine (13/13) and FDG uptake (12/13). The plateau of methionine uptake in tumor was reached by 10 minutes, and thereafter remained constant. FDG tumor uptake was slower and for some patients continued to rise beyond 45 minutes. The clearance of blood activity for C-11-methionine was more rapid than FDG and the plateau was 10 and 45 minutes respectively. In 5 patients scanned after therapy, 4 responded to treatment, which was reflected by a corresponding decrease in C-11-methionine and FDG tumor uptake. No change was observed in the relative shape of the uptake curves however, between the C-11-methionine and the FDG uptake, either in the 4 who responded to treatment or for one patient who did not respond. The SUV of C-11-methionine was significantly higher than for FDG (P <.008). Both C-11-methionine and FDG are taken up in index lesions in patients with progressive prostate cancer. The advantages of C-11-methionine over FDG are the higher tumor to blood ratio, the more rapid tumor uptake allowing earlier imaging, and a flatter plateau rendering lesion activity on whole body images more uniform and less susceptible to gradual change than FDG. This indicates the feasibility of whole body PET imaging with decay corrected C-11-methionine. Additional studies are planned to define optimal imaging times after different therapies in comparison to FDG and bone scans.
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PMID:Differential Metabolism and Pharmacokinetics of L-[1-(11)C]-Methionine and 2-[(18)F] Fluoro-2-deoxy-D-glucose (FDG) in Androgen Independent Prostate Cancer. 1451 41

The ALP1 [aci-reductone dioxygenase (ARD)-like protein 1] gene was identified in a comprehensive cDNA subtraction aimed at identifying genes regulated by androgens in the rat ventral prostate. ALP1 is homologous to the ARD/ARD' that were discovered in Klebsiella pneumoniae as enzymes that have the same polypeptide sequence and differ only in their metal content. This family of proteins is evolutionarily conserved from bacteria to humans and is involved in the methionine salvage pathway. Northern and Western blot confirmed the regulation of ALP1 by androgens in the rat ventral prostate. ALP1 mRNA is expressed in a variety of tissues; however, its regulation by androgens was specific to the prostate. ALP1 is expressed by the glandular epithelial cells of the rat prostate, with little or no expression in the stromal cells. ALP1 is down-regulated in the different rat Dunning tumor cell lines compared with the normal or castrated rat prostate. Expression studies showed that ALP1 overexpression is not tolerated by AT6.1 cells. Further studies demonstrated that ALP1 is also down-regulated in the human prostate cancer cell lines LNCaP, PC3, and DU145, and overexpression induces cell death in these cells. Taken together, our observations suggest that ALP1 may have an important role in androgen regulated prostate homeostasis as well as in prostate cancer progression by regulating cell death of prostate cancer cells.
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PMID:Identification and characterization of an androgen-responsive gene encoding an aci-reductone dioxygenase-like protein in the rat prostate. 1468 10

PTEN is a tumor suppressor gene that is frequently mutated in human tumors. It functions primarily as a lipid phosphatase and plays a key role in the regulation of phosphatidylinositol-3'-kinase. PTEN appears to play a crucial role in modulating apoptosis by reducing the levels of PtdIns(3,4,5)P3, a phospholipid that activates AKT, a central regulator of apoptosis. To understand the role of PTEN in regulating cell proliferation and apoptosis, we stably overexpressed PTEN in PC3 cells, which are prostate cancer cells that lack PTEN. Overexpression of PTEN in two different clones inhibited cell proliferation and increased serum starvation-induced apoptosis, as compared to control cells. Interestingly, PTEN overexpression resulted in a 44-60% reduction in total insulin-like growth factor-I receptor (IGF-IR) protein levels and a 49-64% reduction in cell surface IGF-IR expression. [35S]methionine pulse experiments in PC3 cells overexpressing PTEN demonstrated that these cells synthesize significantly lower levels of the IGF-IR precursor, whereas PTEN overexpression had no effect on IGF-IR degradation. Taken together, our results show that PTEN can regulate cell proliferation and apoptosis through inhibition of IGF-IR synthesis. These results have important implications for understanding the roles of PTEN and the IGF-IR in prostate cancer cell tumorigenesis.
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PMID:PTEN inhibits cell proliferation and induces apoptosis by downregulating cell surface IGF-IR expression in prostate cancer cells. 1473 13

Support mechanisms involved in growth of androgen-independent prostate cancer are primarily unknown. Hepatocyte growth factor (HGF)/Met has been suggested to be one of them based primarily on immunohistochemical studies. We conducted a series of experiments to assess the role of the HGF/Met system in an androgen-dependent human prostate carcinoma, CWR22 and its androgen-independent derivative, CWR22R. We found that action of HGF changed from paracrine to autocrine in progression to androgen-independent state. CWR22 tumors did not express HGF but expressed Met, whereas prostate stromal cells expressed HGF at a high level. Growth of CWR22 was stimulated either by addition of HGF to the culture or by the presence of prostate stromal cells. On the other hand, CWR22R cells expressed both HGF and Met. Knockdown of Met expression by RNA interference method suppressed the growth of CWR22R cells. Our data suggest that HGF is intimately involved in growth of human prostate cancer and that progression from the androgen-dependent to the androgen-independent state is associated with an adaptive switch in support mechanism from paracrine to autocrine. Our data offer one mechanism to account for androgen-independent human cancer growth.
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PMID:Phenotypic switch from paracrine to autocrine role of hepatocyte growth factor in an androgen-independent human prostatic carcinoma cell line, CWR22R. 1527 27

The hepatocyte growth factor/scatter factor (HGF/SF) and its receptor, the Met protein tyrosine kinase, form a classic ligand-receptor system for epithelial-mesenchymal communications in the normal and cancerous prostate. This review illustrates the expression and activities of HGF/SF and Met during prostate development, homeostasis, and carcinogenesis. The participation of HGF/SF in the morphogenetic program of rodent prostate development, the role of Met in normal human prostate epithelium, and underlying mechanisms of deregulated Met expression in localized and metastatic prostate cancer are discussed. On the basis of the commonly observed overexpression of Met in metastatic prostate cancer, HGF/SF-Met-targeted imaging and therapeutic agents can now be applied toward diagnosis and treatment.
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PMID:Prostate cancer and the met hepatocyte growth factor receptor. 1532 88

FDG-PET has a limited role in diagnosis of prostate cancer mainly because of the low uptake of FDG in the tumor and normal excretion of FDG through urine. FDG-PET has shown some promise in the assessment of lymph nodes and bone metastases. There is a large degree of variability when FDG-PET is compared with bone scintigraphy. New C11-labeled radiotracers (acetate, choline, and methionine) have shown promising initial results but further studies are required to determine their role in such settings. These radiotracers provide a unique opportunity for dynamic, multitracer, and quantitative studies, which improve the sensitivity and specificity on PET in this population. Short half-lives and of C-11, however with the limits to their use requires an on-site cyclotron. Recent synthesis schemes with [18F]-labeling, however, may overcome this limitation. FDG-PET has a significant potential to assist with the diagnosis and management of testicular cancer. PET has been most useful in defining the presence or absence of disease in patients with residual masses. PET has shown promising results for the initial diagnosis of this cancer, but further for studies ar required to determine its role in the management of this malignancy. PET can be used in conjunction with conventional imaging techniques to diagnose retroperitoneal masses in patients with primary testicular cancer. FDG-PET has shown very encouraging results in a limited number of studies, and has also demonstrated a good sensitivity for initial staging. FDG-PET seems to be superior to conventional imaging modalities for detecting local disease and recurrence, and distant metastases.
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PMID:PET in the management of urologic malignancies. 1614 85

Peptide deformylase activity was thought to be limited to ribosomal protein synthesis in prokaryotes, where new peptides are initiated with an N-formylated methionine. We describe here a new human peptide deformylase (Homo sapiens PDF, or HsPDF) that is localized to the mitochondria. HsPDF is capable of removing formyl groups from N-terminal methionines of newly synthesized mitochondrial proteins, an activity previously not thought to be necessary in mammalian cells. We show that actinonin, a peptidomimetic antibiotic that inhibits HsPDF, also inhibits the proliferation of 16 human cancer cell lines. We designed and synthesized 33 chemical analogs of actinonin; all of the molecules with potent activity against HsPDF also inhibited tumor cell growth, and vice versa, confirming target specificity. Small interfering RNA inhibition of HsPDF protein expression was also antiproliferative. Actinonin treatment of cells led to a tumor-specific mitochondrial membrane depolarization and ATP depletion in a time- and dose-dependent manner; removal of actinonin led to a recovery of the membrane potential consistent with indirect effects on the electron transport chain. In animal models, oral or parenteral actinonin was well tolerated and inhibited human prostate cancer and lung cancer growth. We conclude that HsPDF is a new human mitochondrial enzyme that may provide a novel selective target for anticancer therapy by use of actinonin-based antibiotics.
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PMID:Human mitochondrial peptide deformylase, a new anticancer target of actinonin-based antibiotics. 1548 58

Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate, which is involved in the methylation of homocysteine to methionine. Genetic polymorphisms that decrease MTHFR activity result in an altered cancer risk depending on folic acid intake. In this study we examined the C677T and A1298C polymorphisms of the MTHFR gene in specimens from 81 patients with prostate cancer and 42 controls selected from patients with benign prostatic hypertrophy (BPH). Genomic DNA was isolated from archived formaldehyde-fixed and paraffin-embedded tissue blocks. MTHFR genotypes were determined by restriction-fragment-length-polymorphism polymerase chain reaction. The MTHFR polymorphism frequencies in the prostate-cancer and BPH specimens were, respectively, 60% and 48% for 677CC, 31% and 48% for 677CT, 9% and 5% for 677TT, 36% and 43% for 1298AA, 53% and 40% for 1298AC, and 11% and 17% for 1298CC. Although such differences fall within the realm of chance variation (P>0.05), the data suggest that the 677CT genotype may be associated with a reduced risk of prostate cancer: the age-adjusted odds ratio (aOR) was 0.6 [95% confidence interval (CI): 0.3-1.4]; the odds-ratio reduction was similar in both blacks and whites (aOR=0.4 in blacks, and 0.6 in whites); and when polymorphisms at the 677 and 1298 loci were analyzed in conjunction, a lower frequency of the 677CT-1298AA genotype was observed in the patients with prostate cancer (aOR=0.3, 95% CI: 0.1-1.1). This particular genotype, moreover, was associated with lower Gleason score tumors (aOR=0.1 for Gleason-score 7 versus 6 tumors, 95% CI: 0.0-0.7) and earlier stage disease (aOR=0.3 for stage III versus II, 95% CI: 0.3-2.6). These findings suggest that polymorphisms of the MTHFR gene may alter the risk of developing prostate cancer.
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PMID:Polymorphisms in the methylenetetrahydrofolate reductase gene and prostate cancer risk. 1549 40


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