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)

Steroid hormones play an important part in prostate biology. Androgens are crucial for the normal development of the prostate gland and in maintaining its functional state in the adult. It seems that the prolonged presence of androgens might also be an important factor in the development of prostate cancer. In addition, androgens and oestrogens appear to play a part in the development of benign prostatic hypertrophy, although the exact nature of their role has not been clearly defined. Stimulation of prostate cancer growth by androgens is well established with androgen withdrawal therapy being the most effective therapy in men with prostate cancer. Additive steroid therapy of metastatic prostate cancer with oestrogens or progestogens has also proved effective. The effects of androgens on prostate cancer cell growth might be mediated through modulation of growth factor expression and alteration of growth factor receptor levels. Androgen response can be modulated by the expression of mutated oncogenes such as ras. Androgen independence can occur through a loss of AR expression or mutation of the AR; however, the patterns of AR expression in normal prostatic tissue from development to adulthood and in cancer are now just beginning to be described. Other steroids, such as the retinoids, show promise as preventive agents, possibly through the modulation of growth factors. Vitamin D compounds modulate prostate cancer cell growth, but their role in prevention and therapy is unclear.
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PMID:Endocrine control of prostate cancer. 762 73

Male sexual differentiation and development proceed under direct control of androgens. Androgen action is mediated by the intracellular androgen receptor, which belongs to the superfamily of ligand-dependent transcription factors. At least three pathological situations are associated with abnormal androgen receptor structure and function: androgen insensitivity syndrome (AIS), spinal and bulbar muscular atrophy (SBMA) and prostate cancer. In the X-linked androgen insensitivity syndrome, defects in the androgen receptor gene have prevented the normal development of both internal and external male structures in 46,XY individuals. Complete or gross deletions of the androgen receptor gene have not been found frequently in persons with complete androgen insensitivity syndrome. Point mutations at several different sites in exons 2-8 encoding the DNA- and androgen-binding domain, have been reported for partial and complete forms of androgen insensitivity. A relatively high number of mutations were reported in two different clusters in exon 5 and in exon 7. The number of mutations in exon 1 is extremely low and no mutations have been reported in the hinge region, located between the DNA-binding domain and the ligand-binding domain and which is encoded by the first half of exon 4. Androgen receptor gene mutations in prostate cancer are very rare and are reported only in exons 4-8. The X-linked spinal and bulbar muscle atrophy (SBMA; Kennedy's disease) is associated with an expanded length (> 40 residues) of one of the polyglutamine stretches in the N-terminal domain of the androgen receptor.
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PMID:Androgen receptor mutations. 762 93

We have established organ cultures of human prostate for in vitro analysis of the hormone responsiveness of prostatic carcinoma. Tissue samples were obtained from total prostatectomies for localized cancer. Normal prostate tissues with age-related hyperplastic changes were obtained from cystoprostatectomies of bladder cancer patients representing the same age group, and they wer cultivated as controls. The explants of prostates were cultured for 7 days in basal medium containing 5% dextran charcoal-treated fetal calf serum, insulin (0.08 IU/ml), and dexamethasone (10(-7) M) with or without dihydrotestosterone (DHT) (10(-7) M) or estradiol (10(-9) M). Control prostates showed involutive changes of morphology when cultured in basal medium. These changes were prevented by DHT, which also maintained a strong epithelial immunostaining for PSA (prostate specific antigen), which was used as a marker for tissue-specific functions. The concentration of PSA in the medium was high. The rate of [3H]thymidine incorporation into DNA was stimulated by DHT in some cultures of control prostates, but no increase was seen in the others. Androgen stimulation of [3H]thymidine incorporation was consistently inhibited by the antihormone cyproterone acetate. The main morphological response of cultured control prostates to estradiol was induction of squamous metaplasia. This was associated with increased incorporation of [3H]thymidine, which was radioautographically localized to the basal layer of epithelium. Estradiol effects were counteracted by the antihormone toremifene. The expression of androgen receptor mRNA and protein in cultured control prostate was demonstrated by Northern blotting and immunohistochemistry, respectively. Also, the expression of estrogen receptor was demonstrated by the polymerase chain reaction analysis of total mRNA from cultured control and cancer prostate. The cultured explants of prostate cancer maintained the overall morphology of the original carcinoma. However, the presence of DHT improved the morphology of cancerous acini in all better differentiated carcinomas (3 grade I and 5 grade II), and corresponding responses to DHT were observed in the rate of DNA labeling with [3H]thymidine. In 2 of 3 grade I carcinomas, DHT increased DNA synthesis, but in grade II cancers the patterns of hormone responses were more variable. The poorly differentiated grade III prostatic carcinomas did not respond to either hormone as measured by [3H]thymidine uptake, and no hormone effects could be seen in morphology. Immunostaining for PSA differed from that in control prostates: besides cancerous acini, the surrounding stroma was also intensively stained, which suggests unpolarized and impaired secretion of PSA by the cancer cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Hormone regulation of human prostate in organ culture. 769 34

Androgen action in many organs, such as prostate and skin, is dependent on the conversion of testosterone by 5 alpha-reductase to 5 alpha-dihydrotestosterone. 5 alpha-Dihydrotestosterone then binds to the androgen receptor to regulate specific gene expression. Inhibitors of 5 alpha-reductase are useful for the selective treatment of prostatic cancer, benign prostate hyperplasia, acne, baldness and female hirsutism, without affecting spermatogenesis, sexual behavior and smooth muscle growth, that do not require the conversion of testosterone to 5 alpha-dihydrotestosterone. Certain unsaturated fatty acids, such as gamma-linolenic acid, are potent 5 alpha-reductase inhibitors, suggesting a linkage between unsaturated fatty acids and androgen action. Mutations in androgen receptor genes are responsible for many cases of androgen-insensitivity. In some prostate cancer cells, some antiandrogens may act like androgens in stimulating the proliferation of the cancer cells because these antiandrogens can bind to a mutated androgen receptor and transactivate target genes. Prostate cancers are usually androgen-dependent initially but can lose dependency and responsiveness. Tumor cells which are resistant to endocrine therapy ultimately proliferate. Androgen-independent or androgen-repressive cells can arise from androgen-sensitive prostate cancer cells by changes in specific gene expression over time in a clonal isolate. This change in androgen responsiveness was accompanied by a change in androgen receptor expression and transcriptional activity as well as expression of some oncogenes.
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PMID:Androgen action: molecular mechanism and medical application. 773 2

The propensity of a cell to undergo apoptosis has been proposed to be a determinant for chemotherapy sensitivity that is not directly dependent on specific drug-target interactions. Androgen-independent prostate cancer is typically refractory to cytotoxic drugs, and we tested whether this is due to a loss of the ability to undergo apoptosis. Exposure of the hormone-insensitive and p53-negative human prostate carcinoma cell line PC-3 to 22 microM cisplatin, 1 microM camptothecin, 10 microM tenoposide, 135 nM vincristine, or 10 microM lovastatin for 72 h caused cell death, internucleosomal DNA fragmentation, and morphological changes typical for apoptosis. One microM cycloheximide prevented anticancer drug-induced apoptosis, whereas high concentration (1 mM) of cycloheximide alone induced apoptosis, indicating that protein synthesis was not needed for these cells to undergo apoptosis. Since cycloheximide affected DNA synthesis and proliferation of PC-3 cells, we tested whether the DNA polymerase inhibitor aphidicolin could also suppress drug-induced apoptosis. In contrast to cycloheximide, aphidicolin inhibited only vincristine-induced apoptosis. Cycloheximide prevented drug-induced changes in cell cycle distribution except for vincristine, while aphidicolin led to an accumulation of cells at the G1-S border independent of the drug used. These data indicate that macromolecular synthesis, active cell cycling, and p53 expression are not required for apoptosis to proceed in this system.
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PMID:Drug-induced apoptosis is not necessarily dependent on macromolecular synthesis or proliferation in the p53-negative human prostate cancer cell line PC-3. 774 12

We describe an in vitro model for prostate cancer treatment that suggests a potential benefit for combined androgen ablation and cytotoxic chemotherapy. Androgen treatment of the LNCaP hormone-dependent human prostate cancer cell line induces increased expression of the BCL-2 protein. Increased levels of this protein are known to mediate inhibition of apoptosis. LNCaP cells, however, did not undergo apoptosis in response to androgen withdrawal. Etoposide exerts its cytotoxicity on LNCaP and other cells by inducing apoptosis. In vitro etoposide cytotoxicity was diminished 83% in the presence of either 10(-8) M dihydrotestosterone or 10(-9) M R1881 in LNCaP cells. The interaction between androgen and etoposide was mediated through the BCL-2 protein, since bcl-2 antisense oligonucleotides blocked the protective effect of androgens on etoposide cytotoxicity.
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PMID:Androgens induce resistance to bcl-2-mediated apoptosis in LNCaP prostate cancer cells. 785 Jul 82

To improve survival in men with metastatic prostatic cancer, a therapeutic modality that can effectively eliminate androgen-independent cancer cells is needed desperately. Combination of such an effective modality with androgen ablation could affect all of the heterogeneous populations within prostate tumors of individual patients, thus optimizing the chances of complete cure. Such a therapeutic approach will probably require two types of agents, one with antiproliferative activity affecting the small number of dividing androgen-independent cells and one with the capacity to increase the rate of cell death among the non-proliferating androgen-independent prostatic cancer cells present, i.e. the majority. Androgen-responsive human prostate cancer cells are able to undergo programmed cell death after androgen ablation (even if the cells are not in the proliferative cell cycle). Androgen-independent human prostate cancer cells, however, do not activate this apoptotic pathway of cell death in response to androgen ablation. In contrast, androgen-independent human prostate cancer cells can be induced to undergo apoptosis following such alternative treatment modalities as: (a) non-androgen ablative cytotoxic drugs, such as fluorinated pyrimidines, which result in the "thymine-less state", and (b) ionizing irradiation. The apoptotic effect induced by radiation can be significantly potentiated by post-irradiation treatment of the cells with suramin. In contrast, this radiation induced apoptosis can be substantially inhibited by pretreatment of cells with suramin, probably through suramin's ability to arrest proliferating cells in the GO/Gl phase of the cell cycle. These results suggest that treatment of prostate cancer patients with suramin prior to irradiation is likely to inhibit radiation palliation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Apoptosis: therapeutic significance in the treatment of androgen-dependent and androgen-independent prostate cancer. 788 65

Androgen-independent Dunning R-3327 AT-3 rat prostatic cancer cells can be induced to undergo programmed cell death in either a proliferation-dependent or independent manner depending upon the therapeutic agent used. In the present study, 5-fluorodeoxyuridine (5-FrdU) was used to induce proliferation-dependent death of the AT-3 cells via its ability to inhibit thymidylate synthetase. Ionomycin and thapsigargin were used to induce proliferation-independent death of these cells via their ability to sustain an elevation in intracellular free Ca2+. Based upon the temporal sequence of DNA fragmentation, morphologic changes, and loss of cell viability, each of the three test agents, at the doses used, induces the programmed death of AT-3 cells with essentially identical kinetics. Based upon these similarities, comparisons of the pattern of gene expression during the proliferation-dependent (i.e., 5-FrdU-induced) vs. proliferation-independent (i.e., ionomycin and thapsigargin-induced) programmed death of AT-3 cells allow identification of genes whose enhanced expression is involved in the initiation vs. completion of programmed cell death. Based upon this approach, enhanced H-ras and TRPM-2 expression is associated with initiation of proliferation-dependent programmed death of AT-3 cells while enhanced c-myc, calmodulin, and alpha-prothymosin expression is associated with initiation of proliferation-independent programmed death of these cells. In contrast, enhanced expression of glucose-regulated 78 kilodalton and tissue transglutaminase genes are associated with the completion of programmed cell death, since their expression is enhanced in both proliferation-dependent and independent programmed cell death of AT-3 cells.
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PMID:Proliferation-dependent vs. independent programmed cell death of prostatic cancer cells involves distinct gene regulation. 799 34

Amphiregulin is a heparin-binding epidermal growth factor (EGF)-related peptide that binds to the EGF receptor (EGF-R) with high affinity. In this study, we report a role for amphiregulin in androgen-stimulated regulation of prostate cancer cell growth. Androgen is known to enhance EGF-R expression in the androgen-sensitive LNCaP human prostate carcinoma cell line, and it has been suggested that androgenic stimuli may regulate proliferation, in part, through autocrine mechanisms involving the EGF-R. In this study, we demonstrate that LNCaP cells express amphiregulin mRNA and peptide and that this expression is elevated by androgenic stimulation. We also show that ligand-dependent EGF-R stimulation induces amphiregulin expression and that androgenic effects on amphiregulin synthesis are mediated through this EGF-R pathway. Parallel studies using the estrogen-responsive breast carcinoma cell line, MCF-7, suggest that regulation of amphiregulin by estrogen may also be mediated via an EGF-R pathway. In addition, heparin treatment of LNCaP cells inhibits androgen-stimulated cell growth further suggesting that amphiregulin can mediate androgen-stimulated LNCaP proliferation. Together, these results implicate an androgen-regulated autocrine loop composed of amphiregulin and its receptor in prostate cancer cell growth and suggest that the mechanism of steroid hormone regulation of amphiregulin synthesis may occur through androgen upregulation of the EGF-R and subsequent receptor-dependent pathways.
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PMID:Epidermal growth factor receptor-dependent stimulation of amphiregulin expression in androgen-stimulated human prostate cancer cells. 804 25

Androgen deprivation remains the primary therapy for patients with metastatic prostate cancer. Response to hormonal manipulation, however, has been quite variable. Androgen receptor (AR) expression has been used to predict clinical response to antiandrogenic treatment. However, methods of detection of AR expression have been limited to receptor biochemical assays in cytosolic or nuclear fractions of frozen tissue homogenates with obvious contamination problems by nonmalignant epithelial and stromal cells. As a result, studies correlating AR expression with response to hormonal therapy have been limited and controversial. More recently, immunohistochemical methods of analysis have become available, but only on frozen tissue. We describe a simple method to evaluate ARs on formalin-fixed, paraffin-embedded tissue sections using antigen retrieval methods. Primary, as well as metastatic, prostate carcinomas showed nuclear staining for ARs. Secretory cells stained uniformly in hyperplastic and normal prostatic glands. The majority of stromal cells had strong nuclear positivity. All other cancers tested (colon, breast, lung, skin, kidney) were negative. This immunohistochemical technique allows evaluation of prostate cancer AR status in routinely processed tissues. Thus, application of this technology to archival material should permit assessment of whether AR expression is predictive of response to endocrine therapy in advanced prostate cancer.
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PMID:Androgen receptor immunohistochemistry on paraffin-embedded tissue. 805 13


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