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)

Inhibin was first identified as a gonad-derived regulator of pituitary FSH; however, it has subsequently been shown to be a tumour suppressor in the gonad and adrenal glands. Whereas non-malignant regions of human primary prostate carcinomas express inhibin alpha-subunit (INHA), malignant tissues lack INHA transcript and protein, which is consistent with epigenetic regulation of the inhibin alpha-subunit gene (INHA) promoter. This study investigated whether methylation of the INHA promoter was responsible for inactivation of INHA transcription and translation in the prostate cancer cell lines, LNCaP, DU145 and PC3. Methylation of the promoter was revealed by bisulphite genomic sequencing and use of inhibitors of methylation and histone deacetylation resulted in reactivation of the INHA transcription and translation. Significant (P<0.05) downregulation of a luciferase reporter gene downstream from a methylated INHA promoter compared with unmethylated INHA promoter occurred in vitro. The data demonstrate that promoter methylation is associated with downregulation of the INHA gene in prostate cancer cell lines, which is consistent with its tumour suppressive role. Therefore INHA has a significant role in prostate tumorigenesis.
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PMID:Epigenetic regulation of inhibin alpha-subunit gene in prostate cancer cell lines. 1476 92

Positive responses to combined androgen elimination therapy and radiation therapy have been well documented in the treatment of prostate cancer patients. The detailed mechanisms how androgen-androgen receptor (AR) cross talks to the radiation-related signal pathways, however, remain largely unknown. Here we report the identification of hRad9, a key member of the checkpoint Rad protein family, as a coregulator to suppress androgen-AR transactivation in prostate cancer cells. In vivo and in vitro interaction assays using Saccharomyces cerevisiae two-hybrid, mammalian two-hybrid, glutathione S-transferase pull-down, and coimmunoprecipitation methods prove that AR can interact with the C terminus of hRad9 via its ligand binding domain. The FXXLF motif within the C terminus of hRad9 interrupts the androgen-induced interaction between the N terminus and C terminus of AR. This interaction between AR and hRad9 may result in the suppression of AR transactivation, demonstrated by the repressed AR transactivation in androgen-induced luciferase reporter assay and the reduced endogenous prostate-specific antigen expression in Western blot assay. Addition of small interfering RNA of hRad9 can reverse hRad9 suppression effects, which suggests that hRad9 functions as a repressor of AR transactivation in vivo. Together, our data provide the first linkage between androgen-AR signals and radiation-induced responses. Further studies of the influence of hRad9 on prostate cancer growth may provide potential new therapeutic approaches.
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PMID:Human checkpoint protein hRad9 functions as a negative coregulator to repress androgen receptor transactivation in prostate cancer cells. 1496 97

Renilla based reporters are frequently used as transfection controls for luciferase transcriptional reporter assays. However, recent evidence suggests that a commonly used reporter (HSV-thymidine kinase driven Renilla) is responsive to androgen receptor (AR) and glucocorticoid receptors in the presence of the cognate ligands, dihydrotestosterone (DHT) and dexamethasone (DEX), respectively [1]. We further validate this important technical difficulty by illustrating that in LNCaP prostate cancer cells, spurious Renilla luciferase activity is a function of (a) the promoter driving Renilla expression, (b) the presence of co-transfected transgenes, and (c) the androgen responsiveness of the cell line used. Using inhibitors of transcription and translation we showed that transcript interference or translational modulation is not a major means by which androgens affect Renilla luciferase activity. As luciferase reporter assays are a frequent means of studying transcriptional co-regulation in the highly androgen dependent LNCaP cell line, our data serves as a cautionary note that alternative normalization techniques should be employed to avoid misinterpretation of data.
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PMID:Androgen responsiveness of Renilla luciferase reporter vectors is promoter, transgene, and cell line dependent. 1504 11

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to be selective in the induction of apoptosis in cancer cells with minimal toxicity to normal tissues and this prompted its potential therapeutic application in cancer. However, not all cancers are sensitive to TRAIL-mediated apoptosis and, therefore, TRAIL-resistant cancer cells must be sensitized first to become sensitive to TRAIL. Treatment of prostate cancer (CaP) cell lines (DU145, PC-3, CL-1, and LNCaP) with nitric oxide donors (e.g. (Z)-1-[2-(2-aminoethyl)-N-(2-ammonio-ethyl)amino]diazen-1-ium-1, 2-diolate (DETANONOate)) sensitized CaP cells to TRAIL-induced apoptosis and synergy was achieved. The mechanism by which DETANONOate mediated the sensitization was examined. DETANONOate inhibited the constitutive NF-kappa B activity as assessed by EMSA. Also, p50 was S-nitrosylated by DETANONOate resulting in inhibition of NF-kappa B. Inhibition of NF-kappa B activity by the chemical inhibitor Bay 11-7085, like DETANONOate, sensitized CaP to TRAIL apoptosis. In addition, DETANONOate downregulated the expression of Bcl-2 related gene (Bcl-(xL)) which is under the transcriptional regulation of NF-kappa B. The regulation of NF-kappa B and Bcl-(xL) by DETANONOate was corroborated by the use of Bcl-(xL) and Bcl-x kappa B reporter systems. DETANONOate inhibited luciferase activity in the wild type and had no effect on the mutant cells. Inhibition of NF-kappa B resulted in downregulation of Bcl-(xL) expression and sensitized CaP to TRAIL-induced apoptosis. The role of Bcl-(xL) in the regulation of TRAIL apoptosis was corroborated by inhibiting Bcl-(xL) function by the chemical inhibitor 2-methoxyantimycin A(3) and this resulted in sensitization of the cells to TRAIL apoptosis. Signaling by DETANONOate and TRAIL for apoptosis was examined. DETANONOate altered the mitochondria by inducing membrane depolarization and releasing modest amounts of cytochrome c and Smac/DIABLO in the absence of downstream activation of caspases 9 and 3. However, the combination of DETANONOate and TRAIL resulted in activation of the mitochondrial pathway and activation of caspases 9 and 3, and induction of apoptosis. These findings demonstrate that DETANONOate-mediated sensitization of CaP to TRAIL-induced apoptosis is via inhibition of constitutive NF-kappa B activity and Bcl-(xL) expression.
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PMID:Nitric oxide sensitizes prostate carcinoma cell lines to TRAIL-mediated apoptosis via inactivation of NF-kappa B and inhibition of Bcl-xl expression. 1504 72

Suicide gene therapy has potential for the treatment of prostate cancer under conditions of androgen deprivation. We show here that the combination of promoter/enhancer of prostate-specific membrane antigen (PEPM) and the Cre-loxP system is a good method to express a suicide gene, namely herpes virus thymidine kinase (TK), in prostate cancer cells. We have examined this system in a castration model in vivo, in comparison with a prostate-specific antigen promoter/enhancer system (PP). In the castrated mice, the tumor luciferase activity with the combination of the PEPM plus the Cre-loxP system was about 50 times greater than that with the control GL3 plasmid. A similar increase was observed in non-castrated mice. In contrast, the luciferase activity of the plasmid PP was decreased significantly in tumors from castrated mice as compared with tumors from non-castrated control mice. Regarding the therapeutic effect, the combination plasmid PEPM-Cre plus CMV-loxP-TK exhibited a strong inhibitory effect on tumor growth in the castrated mice, as in the non-castrated mice. In contrast, PP-TK plasmid did not show any significant growth inhibition in the castrated mice. These findings indicate that the combination of PEPM and Cre-loxP system may have a good treatment effect under androgen ablation conditions in vivo, and our system may therefore be applicable to patients who have previously received androgen deprivation therapy.
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PMID:Treatment efficiency of a suicide gene therapy using prostate-specific membrane antigen promoter/enhancer in a castrated mouse model of prostate cancer. 1507 97

The IGF system plays an important role in prostate cancer initiation and progression. Most of the biological actions of IGF-I and IGF-II are mediated by activation of the IGF-I receptor (IGF-IR). Evidence accumulated in recent years indicates that acquisition of the malignant phenotype is initially IGF-IR dependent, but progression toward metastatic stages is usually associated with a decrease in IGF-IR levels. The Kruppel-like factor 6 (KLF6) is a zinc finger-containing transcription factor that was shown to be mutated in a significant portion of prostate and other types of cancer. To examine the potential regulation of IGF-IR gene expression by KLF6, we measured KLF6 levels in prostate-derived cell lines displaying different levels of IGF-IR. The results of Western analysis showed that KLF6 levels were higher in nontumorigenic P69 cells expressing high IGF-IR levels than in metastatic M12 cells containing reduced IGF-IR levels. Transient coexpression of wild-type, but not mutated, KLF6 together with an IGF-IR promoter-luciferase reporter plasmid resulted in an approximately 3.4-fold stimulation of IGF-IR promoter activity. Furthermore, KLF6 expression induced a significant increment in endogenous IGF-IR levels. Deletion analysis of the IGF-IR promoter revealed that a cluster of four GC boxes located between nucleotides -399 and -331 mediates a significant portion of the transactivating effect of KLF6. KLF6, although unable to stimulate IGF-IR promoter activity in Sp1-null Drosophila-derived Schneider cells, significantly enhanced the effect of Sp1. To assess the potential interactions between KLF6 and p53 in the regulation of IGF-IR gene expression, transfections were performed in the colorectal cancer cell line HCT116(+/+), which expresses p53, and its HCT116(-/-) derivative, which lacks p53. KLF6 exhibited an enhanced activity in p53-containing, compared with p53-null, cells. In addition, we were able to detect a physical interaction between KLF6 and p53. In summary, we have identified the IGF-IR gene as a novel downstream target for transcription factor KLF6. The regulation of IGF-IR gene expression by KLF6 may have significant implications in terms of cancer initiation and/or progression.
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PMID:Transcriptional activation of the insulin-like growth factor I receptor gene by the Kruppel-like factor 6 (KLF6) tumor suppressor protein: potential interactions between KLF6 and p53. 1513 Oct 18

Osteosarcoma (OS), a malignant bone neoplasia in childhood, has poor prognosis if metastases appear in the lung. A novel therapeutic approach could consist in a gene therapeutic treatment of OS metastases. However, if promiscuous viral vectors are applied for the delivery of potentially toxic transgenes, their misdelivery into normal tissues could cause severe complications. This problem could be circumvented by application of OS-specific promoters for transgene expression control. We analysed the function of promoters described to be tumour-, osteosarcoma- or osteoblast-specific. Expression rates driven by osteoblast- specific fragments from the collagen1A1-promoter, the human Osteocalcin-promoter, the bone-sialoprotein promoter and the beta-catenin promoter depending on vitamin supplementation were analysed in five OS cell lines, in normal lung fibroblasts and in a non-osteoblastic prostate cancer cell line (LNCaP) by dual luciferase assays. In addition, an unspecific but doxycyclin-repressible promoter construct (pAd.3r-luc) was examined. We found that all constructs were active in OS cell lines to varying extents. The complete human Osteocalcin promoter and the bone-sialoprotein promoter were partially induced by vitamin D3 or C respectively while the pAd.3r-luc activity could be shut down by doxycyclin. In contrast, the human Osteocalcin-promoter was not activated by vitamin D3 in LNCaP cells; its action remained relatively low. Interestingly, excepting the beta-catenin promoter, we measured strong activities of all promoters in lung fibroblast cells. Our study demonstrates that promoter activity should be evaluated not only for the target cells of the gene therapeutic approaches, but also for neighbouring normal tissues. Unspecific but repressible promoters could represent an alternative.
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PMID:Limited specificity of promoter constructs for gene therapy in osteosarcoma. 1537 10

Human protease-activated receptor-1 (hPar1) plays a role in malignant and physiological invasion processes. We have identified a functional androgen response element (ARE) located in the hPar1 promoter upstream of the transcription start site at -1791 to -1777. Dihydrotestosterone treatment of the prostate cancer cell line LNCaP increased endogenous hPar1 mRNA levels, consistent with the threefold increase in promoter activity of hPar1-luciferase reporter construct. Specific binding of the hPar1-derived ARE to LNCaP nuclear extracts was demonstrated by electrophoretic mobility shift assay. This binding was abrogated by antiandrogen receptor (anti-AR) antibodies or excess cold oligonucleotide but not by a mutated oligonucleotide. Moreover, using chromatin immunoprecipitation assays, we confirm the in vivo interaction between the AR and ARE domain of the hPar1 promoter. In parallel, we show that hormone ablation therapy markedly reduces the otherwise high hPar1 expression levels in prostate cancer biopsy specimens. We suggest that the hPar1 gene is regulated transcriptionally by androgens, representing one of several target genes effectively reduced during hormone ablation therapy. A major limitation of hormonal deprivation is that it causes only a temporary remission, and the cancer eventually reappears in a more malignant, androgen-independent form. hPar1 is also overexpressed in CL1 cells, an aggressively metastasizing, hormone-independent subclone of LNCaP, and in PC3 prostate adenocarcinoma lacking AR in a mechanism yet to be fully elucidated. These data may imply that hPar1 expression correlates with prostate cancer progression in androgen-dependent and -independent phases and therefore, provides an instrumental, therapeutic target for treatment in prostate cancer.
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PMID:Identification of a novel functional androgen response element within hPar1 promoter: implications to prostate cancer progression. 1562 96

Bone metastasis is a common untreatable complication associated with prostate cancer. Metastatic cells seed in skeletal sites under active turnover containing dense marrow cellularity. We hypothesized that differences in these skeletal-specific processes are among the critical factors that facilitate the preferential localization of metastatic prostate cancer in bone. To test this, athymic mice were administered PTH to induce bone turnover and increase marrow cellularity daily 1 wk before and after intracardiac inoculation of luciferase-tagged PC-3 cells. Tumor localization was monitored by bioluminescence imaging weekly for 5 wk. At the time of tumor inoculation, PTH-treated mice demonstrated significant increases in serum levels of bone turnover markers such as osteocalcin and tartrate-resistant acid phosphatase 5b and in the number of tartrate-resistant acid phosphatase-positive osteoclasts per millimeter of bone when compared with the other groups. Likewise, PTH treatment stimulated a qualitative increase in marrow cellular proliferation as determined by 5-bromo-2'-deoxyuridine immunostaining. Skeletal metastases formed in the hind limb and craniofacial regions of young mice with no difference between groups. In adult mice, however, bioluminescent signals in the hind limb and craniofacial regions were 3-fold higher in PTH-treated mice vs. controls. Fluorochrome labeling revealed increased bone formation activity in trabecular bone adjacent to tumors. When zoledronic acid, a nitrogen-containing bisphosphonate that inhibits osteoclast-mediated bone resorption, was administered concurrently with PTH, a significant reduction in the incidence of bone tumors was observed. Overall, these studies provide new evidence that skeletal sites rich in marrow cellularity under active turnover offer a more congenial microenvironment to facilitate cancer localization in the skeleton.
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PMID:Bone turnover mediates preferential localization of prostate cancer in the skeleton. 1563 91

The androgen receptor (AR) dynamically assembles and disassembles multicomponent receptor complexes in order to respond rapidly and reversibly to fluctuations in androgen levels. We are interested in identifying the basal factors that compose the AR aporeceptor and holoreceptor complexes and impact the transcriptional process. Using tandem mass spectroscopy analysis, we identified the trimeric DNA-dependent protein kinase (DNA-PK) complex as the major AR-interacting proteins. AR directly interacts with both Ku70 and Ku80 in vivo and in vitro, as shown by co-immunoprecipitation, glutathione S-transferase pull-down, and Sf9 cell/baculovirus expression. The interaction was localized to the androgen receptor ligand binding domain and is independent of DNA interactions. Ku interacts with AR in the cytoplasm and nucleus regardless of the presence or absence of androgen. Ku acts as a coactivator of AR activity in a luciferase reporter assay employing both Ku-defective cells and Ku small interfering RNA knock-down in a prostate cancer cell line. DNA-PK catalytic subunit (DNA-PKcs) also acts as a coactivator of androgen receptor activity in a luciferase reporter assay employing DNA-PKcs defective cells. AR nuclear translocation is not affected in Ku defective cells, implying Ku functionality may be mainly nuclear. Chromatin immunoprecipitation experiments demonstrated that both Ku70 and Ku80 interact with the prostate-specific antigen promoter in an androgen-dependant manner. Finally, in vitro transcription assays demonstrated Ku involvement in transcriptional recycling with androgen dependent promoters.
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PMID:Ku is a novel transcriptional recycling coactivator of the androgen receptor in prostate cancer cells. 1564 Jan 54


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