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)

Cancer of the prostate is one of the leading causes of cancer related deaths in men. An important role in the development of prostate cancer is played by androgens and androgen ablation is therefore currently used in cancer treatment. In the past, estrogens were widely used in treatment of prostate cancer, but there are indications that estrogens could also be involved in carcinogenesis. Lately, much research has been done on the modulation of the binding of steroid hormones to their receptors by polyunsaturated fatty acids (PUFAs), which could interfere with the steroid hormone's message. Therefore, the aim of this study was to determine in whole DU-145 human prostate cells the effect of EFAs and their metabolites on the binding and affinity of the estrogen receptor (ER) and androgen receptor (AR) to estradiol (E(2)) and testosterone (T), respectively. Fatty acids were dissolved in ethanol and added to the cell culture in a final ethanol concentration of 0.2% on the fourth day of incubation. The results showed that the PUFAs under investigation inhibited the AR's capacity, in contrast to the ER's capacity which was stimulated. However, the dissociation constants (K(d)) of the AR and ER complexes in the presence of the PUFAs, were as follows. Except for eicosapentaenoic acid (EPA) which decreased the AR dissociation constant and EPA and alpha-linolenic acid (ALA) which increased the ER dissociation constant, the remaining FAs had no significant effect on the K(d) values of both the AR and ER complexes. According to these priliminary results it is postulated that men should benefit with a diet rich in certain essential polyunsaturated fatty acids although its function remains to be clarified.
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PMID:Effect of fatty acids on estradiol and testosterone binding to whole DU-145 prostate cells. 1205 12

Selective estrogen receptor modulator is a proven agent for chemoprevention and chemotherapy of cancer. Raloxifene, a mixed estrogen agonist/antagonist, was developed to prevent osteoporosis and potentially reduce the risk of breast cancer. In this study, we examined the effect of raloxifene on the TSU-PR1 cell line. This cell line was originally reported to be a prostate cancer cell line, but recently it has been shown to be a human bladder transitional cell carcinoma cell line. The TSU-PR1 cell line contains high levels of estrogen receptor beta. Following treatment with raloxifene, evidence of apoptosis, including change in nuclear morphology, DNA fragmentation, and cytochrome c release, was observed in a dose-dependent manner in the TSU-PR1 cells (10(-9) to 10(-6) m range). We observed no detectable change in the steady-state levels of Bax, Bcl-2, and Bcl-X(L) following raloxifene treatment. However, raloxifene induced caspase-dependent cleavage of BAD to generate a 15-kDa truncated protein. Overexpression of a double mutant BAD resistant to caspase 3 cleavage blocked raloxifene-induced apoptosis. These results demonstrate that raloxifene induces apoptosis through the cleavage of BAD in TSU-PR1 cells. This molecular mechanism of apoptosis suggests that raloxifene may be a therapeutic agent for human bladder cancer.
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PMID:Raloxifene, a mixed estrogen agonist/antagonist, induces apoptosis through cleavage of BAD in TSU-PR1 human cancer cells. 1208 14

Raloxifene, a selective estrogen receptor (ER) modulator, is a mixed estrogen agonist/antagonist that has been shown to prevent osteoporosis and breast cancer in women. Because the prostate contains a high level of ER-beta, the present study investigated the effect of raloxifene in the androgen-sensitive human prostate cancer cell line LNCaP. Previously, it has been demonstrated that LNCaP cells express ER-beta but not ER-alpha and that tamoxifene induces apoptosis in these cells. After treatment with raloxifene, a dramatic increase in cell death occurred in a dose-dependent manner (10(-9) to 10(-6) M range). Using the terminal deoxynucleotidyl transferase-mediated nick end labeling apoptotic assay, we demonstrated that the nuclear fragmentation was due to apoptosis. The dramatic change in cellular morphology after treatment with raloxifene was no longer observed when cells were pretreated with a pan-caspase inhibitor, Z-VAD-FMK, and a specific caspase-9 inhibitor, Z-LEHD-FMK. Furthermore, immunoblot demonstrated an activation of caspase-9 in LNCaP cells. Because LNCaP cells contain a mutated androgen receptor that allows cellular proliferation in the presence of antiandrogens, prostate-specific antigen assay and transfection with a reporter construct containing luciferase gene under the control of androgen response element (pARE) were carried out. The results demonstrated that raloxifene does not significantly alter androgen receptor activity in LNCaP cells. Taken together, these results demonstrate that raloxifene, a selective ER modulator, induces apoptosis in the androgen-sensitive human prostate cancer cell line LNCaP through an androgen-independent pathway.
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PMID:Raloxifene, a selective estrogen receptor modulator, induces apoptosis in androgen-responsive human prostate cancer cell line LNCaP through an androgen-independent pathway. 1209 69

Sex steroid hormone receptors play a central role in all stages of prostate cancer. Here, we tested whether estrogen receptor (ER) signaling contributes to telomerase activation, an early event in prostate tumorigenesis. Following 17beta-estradiol (E(2)) treatment, both mRNA encoding the catalytic subunit of human telomerase (hTERT) and telomerase activity were promptly induced in human prostate normal epithelial cells, fresh explants from benign prostate hyperplasia, and prostate cancer explants and cell lines. Reporter expression studies and in vivo chromatin immunoprecipitation assays revealed E(2)-dependent hTERT promoter induction and showed that both ERalpha and ERbeta bound this sequence. Crucially, addition of the anti-estrogen 4-hydroxytamoxifen caused a differential recruitment in vivo of ERalpha and ERbeta onto the hTERT promoter and inhibited telomerase activity. Treatment with the aromatase inhibitor letrozole, which prevented testosterone-mediated interaction between ER and the hTERT estrogen response element, resulted in a negative regulation of telomerase activity. Thus, intracellular conversion of androgens to estrogens may contribute to the etiopathogenesis of prostate cancer. Given the present evidence for direct control of hTERT gene expression and telomerase activity in the prostate by the ER, we suggest that this transcriptional regulator represents a possible therapeutic target in prostate cancer.
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PMID:Signaling through estrogen receptors modulates telomerase activity in human prostate cancer. 1212 14

The objective of this study was to study the expression of estrogen receptor-beta (ER-beta) in prostatic adenocarcinoma and correlate it with Gleason grade and clinical outcome. Immunohistochemical evaluation was performed on prostate needle biopsies from 53 patients (T1-T3pN0M0). ER-beta and ER-alpha transcripts were also studied by semiquantitative reverse transcriptase polymerase chain reaction in PC-3 and LNCaP prostate carcinoma cell lines. ERbeta was expressed in 93% of adenocarcinomas and was positively associated with primary Gleason grade (P = 0.028 for percentage of positive cells and P = 0.046 using a semiquantitative scale) and Gleason score (P = 0.010 for percentage of positive cells and P = 0.014 using a semiquantitative scale). ER-beta expression in the benign epithelium of prostates with adenocarcinoma was detected in 92% of cases and in the stroma in 47% of cases. A trend for longer time to treatment failure was noted for cases with low ER-beta expression after curatively intended radiotherapy (P = 0.082). PC-3, an aggressive prostate cancer cell line with invasive properties in nude mice, expressed higher levels of ER-beta than LNCaP, a nonmetastasizing cell line, whereas no difference for ER-alpha transcripts could be observed. Our findings suggest that ER-beta, as detected by PPG5/10 antibody, may have a role in the process of dedifferentiation of prostate adenocarcinomas, with higher levels present in less differentiated tumors.
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PMID:Prostate carcinoma expression of estrogen receptor-beta as detected by PPG5/10 antibody has positive association with primary Gleason grade and Gleason score. 1215 65

Raloxifene, a selective estrogen receptor (ER) modulator, is a mixed estrogen agonist/antagonist that has been shown to prevent osteoporosis and breast cancer in women. Because the prostate contains high levels of ER-beta, the present study investigated the effect of raloxifene in three well-characterized, androgen-independent human prostate cancer cell lines: (a) PC3; (b) PC3M; and (c) DU145. Reverse transcriptase-PCR and Western blot analysis for ER-alpha and ER-beta demonstrated that all three cell lines express ER-beta, whereas only PC3 and PC3M cells were positive for ER-alpha. After the treatment with raloxifene, a dramatic increase in cell death was observed in a dose-dependent manner in the three prostate cancer cell lines (10(-9) to 10(-6) M range). Because the three prostate cancer cell lines demonstrated similar morphological changes after the raloxifene treatment, PC3 (ER-alpha/ER-beta+) and DU145 (ER-beta+ only) cells were selected to further characterize the raloxifene-induced cell death. Using the nucleus-specific stain 4',6-diamidino-2-phenylindole, nuclear fragmentation was observed in a time-dependent manner in both cell lines after exposure to 10(-6) M raloxifene. Using the terminal deoxynucleotidyl transferase-mediated nick end labeling apoptotic assay, it was demonstrated that the nuclear fragmentation was caused by apoptosis. To investigate the possibility that caspase activation is involved in raloxifene-induced apoptosis, cells were treated with the pan-caspase inhibitor ZVAD. The results demonstrated that the dramatic change in cellular morphology after treatment with raloxifene was no longer observed when cells were pretreated with ZVAD. Immunoblot demonstrated activation of caspases 8 and 9 in PC3 and DU145 cells, respectively. Taken together, these results demonstrate that the mixed estrogen agonist/antagonist, raloxifene, induces apoptosis in androgen-independent human prostate cancer cell lines.
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PMID:Raloxifene, a mixed estrogen agonist/antagonist, induces apoptosis in androgen-independent human prostate cancer cell lines. 1223 8

The mammalian phytoestrogens enterodiol (END) and enterolactone (ENL) are produced in the colon by the action of bacteria on the plant precursors matairesinol (MAT), secoisolariciresinol (SECO), their glycosides, and other precursors in the diet. Both END and ENL have been shown to possess weakly estrogenic and antiestrogenic activities, and it has been suggested that the high production of these antiestrogenic mammalian lignans in the gut may serve to protect against breast cancer in women and prostate cancer in men. Various in vitro experiments suggested END and ENL significantly inhibited the growth of human colon tumor cells, and the E2-induced proliferation of MCF-7 breast cancer cells was inhibited by ENL. The protective effects of mammalian lignans may be due to their ability to compete with E2 for the type II estrogen receptor, to induce sex hormone binding globulin (SHBG), to inhibit placental aromatase, and to act as antioxidants. This review mainly deals with the chemistry, quantitative analysis, biological properties and health effects of END and ENL.
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PMID:Mammalian phytoestrogens: enterodiol and enterolactone. 1227 Feb 21

The androgen receptor (AR) is a ligand-dependent transcription factor that has an essential role in the normal growth, development, and maintenance of the prostate gland. The AR is part of a large family of steroid receptors that also includes the glucocorticoid, progesterone, and mineralocorticoid receptors. Steroid receptor family members share significant homology at their DNA and ligand-binding domains. However, these receptors exhibit a high degree of sequence variability at their NH(2)-terminal domain, which suggests the possibility of receptor-specific interactions with co-regulator proteins. Transcriptional co-regulators that interact with the AR may have a role in defining AR activity and may be involved in directing AR-specific responses. Here we have identified Ran-binding protein in the microtubule-organizing center (RanBPM) to be a novel AR-interacting protein by yeast two-hybrid assay and have confirmed this interaction by glutathione S-transferase- and His-tagged pull-down assays. In addition, transient overexpression of RanBPM in prostate cancer cell lines resulted in enhanced AR activity in a ligand-dependent fashion. Glucocorticoid receptor activity was also enhanced when RanBPM was overexpressed, whereas estrogen receptor activity remained unchanged. These data demonstrate that RanBPM interacts with steroid receptors to selectively modify their activity.
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PMID:RanBPM, a nuclear protein that interacts with and regulates transcriptional activity of androgen receptor and glucocorticoid receptor. 1236 45

Nuclear receptors comprise a family of transcription factors that regulate gene expression in a ligand dependent manner. They can activate or repress target genes by binding directly to DNA response elements as homo- or hetero-dimers or by binding to other classes of DNA-bound transcription factors. These activities have been linked to the formation of complexes with molecules that appear to serve as coactivators or corepressors, causing local modification of chromatin structure in order to regulate expression of their target genes. Several members of nuclear receptor family are directly associated with human malignancies including breast cancer, prostate cancer and leukaemia. The pathogenesis of each of these diseases is underpinned by the activities of a member of the superfamily; estrogen receptor-alpha (ER alpha) in breast cancer, androgen receptor (AR) in prostate cancer, and retinoic acid receptor alpha (RAR alpha) in acute promyelocytic leukaemia.
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PMID:Modulation of nuclear receptor dependent transcription. 1241 47

Cancer chemoprevention is a new approach in the management of cancer. Traditional cytotoxic chemotherapeutic approaches cannot cure most advanced solid malignancies. Chemoprevention can be defined as the use of non-cytotoxic drugs and natural agents to block the progression to invasive cancer. Chemoprevention can either prevent DNA damage that initiates the neoplastic transformation process or reverses the progression of pre-invasive lesions. Epidemiological observations, experimental evidence from animal carcinogenesis models, knock-out models, cancer cell lines and clinical trials have shown the efficacy of this approach. Recent advances in our understanding of carcinogenesis have led to the synthesis of new drugs that target specific receptors. Non-steroidal anti-inflammatory drugs target the prostaglandin pathway. The identification of the role of cyclooxygenase-2 in epithelial carcinogenesis led to the synthesis of selective cyclooxygenase-2 inhibitors (Celecoxib). Celecoxib was subsequently approved for the prevention of colon polyps in familial adenomatous polyposis after the completion of a randomized clinical trial. The large chemoprevention clinical trial with the selective estrogen receptor modulator, tamoxifen, showed the benefit of tamoxifen in the prevention of breast cancer in high-risk women. Retinoids and rexinoids target the retinoid receptors and have a role in chemoprevention of aerodigestive, hepatic and cervical neoplasia. Selenium, an inhibitor of the glutathione peroxidase system, is being tested in the chemoprevention of prostate cancer and lung cancer. The different isoforms of vitamin E (tocopherols) may be chemopreventive. Recent evidence indicates that gamma-tocopherol may be a more powerful chemopreventive than the alpha-tocopherol. The review details the rationale, experimental and clinical evidence and the drug targets of the chemopreventive agents that are currently in various phases of clinical development.
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PMID:Cancer chemoprevention drug targets. 1252 89


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