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)

Genetic defects of the human androgen receptor (AR) can cause a wide spectrum of androgen insensitivity syndromes (AIS) ranging from phenotypic females in those with complete AIS; ambiguous genitalia in partial AIS; to male infertility in minimal AIS. The majority of these defects are due to point mutations resulting in amino acid substitutions. It is however unclear why certain mutations result in partial AIS, whereas others in the same exon cause the complete syndrome. We present a case of partial AIS due to a point mutation affecting codon 758 of the AR ligand-binding domain (LBD) that changed the sense of the codon from asparagine to threonine (N758T). The mutant receptor displayed normal binding affinity to DHT but abnormal dissociation kinetics in both patient's fibroblasts and transfected COS-7 cells. The mutant AR was thermolabile, and resulted in approximately 50% reduction in receptor transactivation capacity when examined with a reporter gene incorporating an androgen-response-element. Although the 3-D structure of AR LBD is not known, the homologous region in a member of the steroid receptor superfamily, retinoid-X receptor (RXR-alpha), has been crystallized, allowing comparison of aligned amino-acid sequences of RXR-alpha and AR. The mutation, N758T, lies in a predicted linker region between the fifth alpha-helix (H5) and the first beta-strand (S1). Generally, mutations leading to partial AIS tend to cluster in the predicted linker regions located between the structural helices of the AR LBD. Most strikingly, the predicted linker regions contain over 70% of the mutant ARs associated with prostate cancer in the LBD. The occurrence of mutations associated with both partial AIS and prostate cancer in the same predicted linker regions, suggest that this clustering is not coincidental and that the predicted linker regions are likely to have important, but subtle, roles in defining androgen binding and ligand specificity.
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PMID:Partial androgen insensitivity and correlations with the predicted three dimensional structure of the androgen receptor ligand-binding domain. 960 27

Protein kinase CK2, a messenger-independent serine/threonine kinase, has been implicated in cell growth. Androgenic stimulus in rat prostate modulates its association with nuclear matrix (NM) and chromatin. Because the growth of human prostate carcinoma cells is influenced by androgens and/or growth factors, we determined the nature of CK2 signaling in the NM in response to androgen and growth factor stimuli. Androgen-sensitive LNCaP and androgen-insensitive PC-3 cells were cultured in media to regulate their growth in the presence of 5alpha-dihydrotestosterone (5alpha-DHT) or growth factors (epidermal growth factor, keratinocyte growth factor, and transforming growth factor alpha). The activity of CK2 was measured in the cytosolic and NM fractions isolated from these cells after treatment with growth stimuli. The changes in CK2 in various fractions were also confirmed by immunoblotting with a specific antibody. LNCaP cells responded to both 5alpha-DHT and growth factors for growth. The presence of these agents in the culture medium evoked a translocation of CK2 to the NM from the cytosol. The PC-3 cells did not respond to 5alpha-DHT for growth but did respond to growth factors. Under these conditions, there was also a translocation of CK2 to the NM concomitant with a decrease in the cytosolic fraction. These results suggest that CK2 translocation to the NM occurs in response to various growth stimuli in cells in culture. Thus, CK2 is a common downstream signal transducer in response to diverse growth stimuli that may relate to the pathobiology of prostate cancer cells.
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PMID:Nuclear matrix targeting of the protein kinase CK2 signal as a common downstream response to androgen or growth factor stimulation of prostate cancer cells. 1007 Sep 76

Protein phosphorylation/dephosphorylation is an important posttranslational modification that plays a critical role in signal transduction. The androgen receptor (AR) is under such control. We demonstrate that androgen receptor phosphorylation determines whether or not AR ligands perform as agonists or antagonists in LNCaP cells. Androgen receptor ligands (such as dihydrotestosterone and beta-estradiol) stimulate receptor expression and phosphorylation and, as a result, they act as agonists or partial agonists. In contrast, agents such as bicalutamide and estramustine inhibit the receptor phosphorylation and act as antagonists. This model is supported by gene expression and transactivation assays. Significant increases in levels of both mRNA and protein of prostate-specific antigen (PSA), a natural AR target gene, occur following the treatment of LNCaP cells with DHT, beta-estradiol, or hydroxyflutamide. In contrast, exposure of LNCaP cells to bicalutamide or estramustine results in a sharp decrease of PSA expression. Agonistic or antagonistic effect of these compounds on PSA expression parallels the level of phosphorylated, but not dephosphorylated androgen receptors. These agonistic or antagonistic effects are also observed in HeLa cells transfected with wild-type AR expression plasmid (pAR0) and AR-driven luciferase expression plasmid GRE-tk-LUC in the presence of different groups of AR blockers. Our data indicate that the functional status of androgen receptors is strongly correlated with the phosphorylation status of the receptors, and that the phosphorylated androgen receptor is the form of the receptor transcriptionally active in regulation. Thus the androgen receptor phosphorylation/dephosphorylation may serve as a new molecular target for screening androgen antagonists for the treatment of prostate cancer.
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PMID:Phosphorylation/dephosphorylation of androgen receptor as a determinant of androgen agonistic or antagonistic activity. 1033 9

In recent years, the enzymes which are involved in the formation of DHT in steroid target tissues have been well investigated, however, enzymes responsible for the catabolism and elimination of steroids in these tissues, in particular the uridine diphospho-glucuronosyltransferase (UGT) family of enzymes, have received much less attention. We have recently demonstrated that human and monkey are unique in having high plasma levels of C19 steroid glucuronides. These circulating conjugates have been proposed to reflect the peripheral conversion of adrenal and gonadal C19 steroids to potent androgens, especially DHT. In humans, the presence of steroid UGT activities is found in the liver and several extrahepatic tissues including the prostate, mammary gland and ovary. In addition, UGT activities were observed in breast and prostate tumor cell lines such as MCF-7 and LNCaP, respectively. In agreement with the presence of steroid conjugating enzymes in extrahepatic tissues, UGT cDNA clones, which encode steroid conjugating proteins, have been isolated from libraries constructed from human and monkey prostate mRNA. The presence of UGT transcripts and proteins in extrahepatic tissues in both species, as determined by Northern blot, ribonuclease protection, specific RT-PCR, in situ hybridization, Western blot and immunocytochemistry analysis, indicate the relevance of steroid glucuronidation in tissues other than the liver. Knowing that both the human prostate and the human prostate cancer LNCaP cell line express steroid metabolizing proteins, including UGT enzymes, regulation of UGT mRNA and protein levels, as well as promoter activity was studied in these cells. The results demonstrate a differential regulation between the two highly related isoforms UGT2B15 and UGT2B17, where only the expression of UGT2B17 was affected following treatments of LNCaP cells with androgens, growth factors or cytokines. Steroid conjugation by UGT enzymes is potentially involved in hormone inactivation in steroid target tissues, thus modifications in UGT expression levels may influence hormonal responses.
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PMID:Characterization of UDP-glucuronosyltransferases active on steroid hormones. 1041 20

The molecular mechanisms involved in differentiation of prostate cancer cells to a neuroendocrine (NE) cell phenotype are not well understood. Here we used the androgen-dependent human prostate cancer cell line LNCaP to perform a systematic and broad analysis of the expression, pharmacology, and functionality of vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase-activating peptide (PACAP) receptors. Reverse transcription polymerase chain reaction experiments, together with pharmacological approaches with a set of specific agonists and antagonists, demonstrated the presence of the three VIP/PACAP receptor subtypes (PAC1, VPAC1, and VPAC2 with a major role for VPAC1, acting through adenylate cyclase (AC) stimulation. An essentially similar pattern was observed by NE differentiated cells (4 days after serum deprivation) in spite of the important morphological changes observed. However, the expression of the prostate-specific antigen (PSA) decreased in NE cells (and increased again by dihydrotestosterone, DHT, treatment). The present demonstration of the induction of NE transdifferentiation in LNCaP cells by increasing concentrations of VIP adds value to previous observations on the role of cAMP in this process, an interesting topic in the comprehension of the molecular changes that are involved in the progression of prostate cancer to androgen independence.
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PMID:Neuroendocrine differentiation of the LNCaP prostate cancer cell line maintains the expression and function of VIP and PACAP receptors. 1172 28

Apigenin, a common dietary flavonoid abundantly present in fruits and vegetables, may have the potential for prevention and therapy for prostate cancer. Here, we report for the first time that apigenin inhibits the growth of androgen-responsive human prostate carcinoma LNCaP cells and provide molecular understanding of this effect. The cell growth inhibition achieved by apigenin treatment resulted in a significant decrease in AR protein expression along with a decrease in intracellular and secreted forms of PSA. These effects were also observed in DHT-stimulated cells. Further, apigenin treatment of LNCaP cells resulted in G1 arrest in cell cycle progression which was associated with a marked decrease in the protein expression of cyclin D1, D2 and E and their activating partner cdk2, 4 and 6 with concomitant induction of WAF1/p21 and KIP1/p27. The induction of WAF1/p21 appears to be transcriptionally upregulated and is p53 dependent. In addition, apigenin inhibited the hyperphosphorylation of the pRb protein in these cells. Apigenin treatment also resulted in induction of apoptosis as determined by DNA fragmentation, PARP cleavage, fluorescence microscopy and flow cytometry. These effects were found to correlate with a shift in Bax/Bcl-2 ratio more towards apoptosis. Apigenin treatment also resulted in down-modulation of the constitutive expression of NF-kappaB/p65. Taken together, these findings suggest that apigenin has strong potential for development as an agent for prevention against prostate cancer.
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PMID:Involvement of nuclear factor-kappa B, Bax and Bcl-2 in induction of cell cycle arrest and apoptosis by apigenin in human prostate carcinoma cells. 1203 41

Chemotherapeutic drug resistance remains a significant obstacle in the control of prostate cancer. The influence of p53 and androgen status on the drug response of new cell lines from normal, benign and primary tumour epithelium was investigated. The prostate cell lines 1542-NPTX, BPH-1, 1542-CP(3)TX, 1532-CP(2)TX, 1535-CP(1)TX and LNCaP were exposed to TD(50) doses of etoposide, vinblastine and estramustine for a period of 24 h and re-incubated for a further 4 days before measuring the cell viability by crystal violet vital dye staining assay. The virus-transformed cell lines were found to be approximately ten times more sensitive to etoposide and vinblastine than the non virus-transformed LNCaP cell line. Estramustine proved to be the least toxic drug. The LNCaP cell line emerged as DHT-sensitive against nanomolar concentrations of 5alpha-dihydrotestosterone in charcoal-stripped growth medium. The virus-transformed cell lines were DHT-insensitive. Induction of p21 by (60)Co gamma-irradiation was used to assess the functionality of the p53 gene. p21 induction in the LNCaP cell line reached a peak 7.5 h post-irradiation. No significant p21 induction occurred in the virus-transformed cell lines. We show that the androgen-independent tumour cell lines are more sensitive to etoposide and vinblastine than the androgen dependent cell line, LNCaP. Except for LNCaP cells, etoposide and vinblastine were found to be three- to ten-fold more effective than estramustine. In the benign hyperplasia cell line, BPH-1, only etoposide is highly effective. Etoposide and vinblastine were found to effectively inactivate the androgen-independent cell lines, in which p53 is dysfunctional.
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PMID:Drug resistance in prostate cancer cell lines is influenced by androgen dependence and p53 status. 1238 16

The non-steroidal antiandrogens flutamide (Eulexin((R))), nilutamide (Anandron((R))) and bicalutamide (Casodex((R))) are widely used in the treatment of advanced prostate cancer, particularly in combination with castration. The naturally occurring ligand 5alpha-DHT has higher binding affinity at the androgen receptor than the non-steroidal antiandrogens. Bicalutamide has an affinity two to four times higher than 2-hydroxyflutamide, the active metabolite of flutamide, and around two times higher than nilutamide for wild-type rat and human prostate androgen receptors. Animal studies have indicated that bicalutamide also exhibits greater potency in reducing seminal vesicle and ventral prostate weights and inhibiting prostate tumour growth than flutamide. Although preclinical data can give an indication of the likely clinical activity, clinical studies are required to determine effective, well-tolerated dosing regimens. As components of combined androgen blockade (CAB), controlled studies have shown survival benefits of flutamide plus a luteinising hormone-releasing hormone analogue (LHRH-A) over LHRH-A alone, and for nilutamide plus orchiectomy over orchiectomy alone. Other studies have failed to show such survival benefits, including those comparing flutamide plus orchiectomy with orchiectomy alone, and nilutamide plus LHRH-A with LHRH-A alone. In a direct comparative study, bicalutamide (50 mg, once daily) was compared with flutamide (250 mg, three times daily), each in combination with an LHRH-A. Both therapies were well tolerated, although more patients could not tolerate flutamide therapy: 25 flutamide plus LHRH-A and 2 bicalutamide plus LHRH-A patients withdrew from therapy due to diarrhoea. There were no statistically significant differences for time to progression or survival between the two antiandrogens. This clinical trial of bicalutamide confirms the prediction from preclinical studies that a 50 mg dose of bicalutamide would be appropriate for use in patients with advanced prostate cancer, and demonstrates that this bicalutamide dose is clinically effective when administered as part of CAB.
Prostate Cancer Prostatic Dis 1998 Dec
PMID:Receptor affinity and potency of non-steroidal antiandrogens: translation of preclinical findings into clinical activity. 1249 72

Recently, we isolated a ubiquitously expressed gene designated TERE1, which has a significant effect on the growth regulation in bladder cancer. The TERE1 gene maps to chromosome 1p36.11-1p36.33 between the micro-satellite markers D1S2667 and D1S434, a chromosome locus that has been identified by loss of heterozygosity studies as a site of a putative tumor suppressor gene or genes for multiple tumor types including prostate carcinoma. The expression of the TERE1 transcript and protein was examined in a series of thirty microdissected prostate tumors by semi-quantitative RT/PCR and immunohistochemistry. There was a significant 61% decrease in the TERE1 transcript in prostate carcinoma (CaP) and a distinct loss of the TERE1 protein in metstatic prostate. Though a loss of heterozygosity at chromosome 1p36 was found in 25% of these prostate tumors, there appeared to be no TERE1 mutations present in these tumor samples. Induced TERE1 expression after transduction or transfection of TERE1 constructs into two prostate carcinoma (LNCaP and PC-3) cell lines significantly decreased proliferation up to 80% with a significant increase in the number of cells in G1. Serum factors but not DHT (dihydrotestosterone) appear to regulate the amount of TERE1 protein in the androgen responsive LNCaP cell line. Additionally, we have identified by microarray analysis various growth regulatory genes that are down-regulated or up-regulated in TERE1-transduced PC-3 cells. Altogether, these data suggest that TERE1 maybe significant in prostate cancer growth regulation and the down regulation or absence of TERE1 may be an important component of the phenotype of advanced disease.
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PMID:TERE1, a novel gene affecting growth regulation in prostate carcinoma. 1249 87

The objective of this study is to synthesize new steroidal compounds based on the progesterone skeleton with a high inhibitory activity for the enzyme 5alpha-reductase. Presently similar compounds are being used for the treatment of androgen dependent diseases such as: hirsutism, androgenic alopecia, bening prostatic hyperplasia and prostate cancer. Dihydrotestosterone 2 (Fig. (1)), a 5alpha-reduced metabolite of testosterone 1 has been implicated as a causative factor in the progression of these diseases, largely through the clinical evaluation of males who are genetically deficient of steroid 5alpha-reductase enzyme. As a result of this study, the inhibition of this enzyme has become a pharmacological strategy for the design and synthesis of new antiandrogenic drugs. The advent of finasteride 8 (Fig. (4)) a 5alpha-reductase inhibitor has grately alleviated the symptoms associated with benign prostatic hyperplasia. In our laboratory we recently synthesized several new 16beta-methyl-pregnadiene-3,20-diones derivatives 27 (Fig.(6)), 38-42 (Fig. (11)), 16beta-phenyl-pregnadiene-3,17a-dione derivatives 32-33 (Fig. (7)), 16beta-phenyl-pregnatriene-3,17a-diones, 30, 31 (Fig. (7)) and 16beta-methyl-pregnatriene-3,20-diones 43-46 (Fig. (11)). These compounds were evaluated as 5alpha-reductase inhibitors in the following biological models: Penicillium crustosum broths, the flank organs of gonadectomized male hamsters, the incorporation of radiolabeled sodium acetate into lipids, the effect of the new steroids on the reduction of the weight of the seminal vesicles and on the in vitro metabolism of [(3)H]T to [(3)H]DHT in seminal vesicles homogenates of gonadectomized male hamsters. All trienones 30, 31, and 43-46 in all biological models showed consistently a higher 5alpha-reductase inhibitory activity than the corresponding dienones 27, 32, 33 and 38-42. We believe that with these compounds the 5alpha-reductase enzyme is inactivated by an irreversible Michael type addition of the nucleophilic portion of the enzyme to the conjugated double bond of the steroid. The trienones having a more coplanar structure react faster with the enzyme and thus show a higher inhibitory activity.
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PMID:Steroid 5alpha-reductase inhibitors. 1257 Aug 38


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