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)

Androgens mediate their effects through an intracellular receptor that is a member of the steroid/thyroid hormone family of receptors. The expression of this protein is tightly regulated in different tissues and among cell types within a single tissue. To define the mechanisms controlling the expression of the androgen receptor, we have isolated and characterized the promoter of the androgen receptor gene in the human prostate cell line LNCaP. The major site of transcription initiation is approximately 1.1 kilobases upstream of the initiator methionine of the androgen receptor protein. The promoter region lacks typical "TATA" and "CAAT" sequence motifs but lies in a GC-rich region and contains a putative Sp1 binding site characteristic of a "housekeeping" promoter and a 44-base segment composed of alternating adenosine and guanosine residues. S1 nuclease protection analyses indicate that the same promoter is employed both in human tissues (prostate, testes), in genital skin fibroblasts, in T47D and MCF-7 breast cancer cells, and in LNCaP prostate cancer cells.
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PMID:Expression of the human androgen receptor gene utilizes a common promoter in diverse human tissues and cell lines. 238 Jan 87

Thyroid cancer is well known to be hormone sensitive as well as breast cancer, prostatic cancer, and endometrial cancer of the uterus. Various experimental results suggest that the growth regulation for thyroid cancer, as well as the normal thyroid gland, appears to depend upon the TSH (Thyroid stimulating hormone) receptor on cell membranes. Differentiated thyroid carcinoma cells possess TSH receptor, although anaplastic carcinoma cells do not; therefore suppression therapy of TSH with thyroid hormone is considered to be effective against differentiated thyroid carcinoma. It has been recognized that some recurrent differentiated thyroid cancers cause regression in size in response to treatment with thyroid hormone. But the administration of the thyroid hormone after the operation for the differentiated thyroid carcinoma does not necessarily enhance the survival rate. To analyze the difference in survival rate is very difficult because of the excellent survival rate of thyroid cancer patients after the operation. It is hoped that further clinical study and laboratory investigation about suppression in adjuvant therapy for differentiated thyroid cancer will give us a conclusive answer.
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PMID:[The effect of thyroid hormone on the growth of thyroid cancer]. 268 57

Differentiated thyroid cancer, like breast cancer, prostatic cancer, and endometrial cancer of the uterus, is well known to be hormone sensitive. Experimental investigations have demonstrated that differentiated thyroid cancer cells have TSH (thyroid-stimulating hormone) receptor on the plasma membrane and that the growth regulation of differentiated thyroid cancer depends upon TSH. Therefore, suppression of TSH with thyroid hormone is rational for the treatment of recurrent thyroid cancer. Recurrent differentiated thyroid cancers reportedly cause regression in response to thyroid hormone administration, but the outcome of adjuvant therapy with thyroid hormone after operation for differentiated thyroid carcinoma is controversial. It is very difficult to analyze the difference in survival rate between the postoperative patient with and without thyroid hormone, because of the excellent postoperative survival rate of differentiated thyroid cancer patients. Further clinical studies and laboratory investigations about TSH suppression in adjuvant therapy for differentiated thyroid cancer are necessary to elucidate the impact of thyroid hormone on survival after operation.
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PMID:[The effect of thyroid hormone on thyroid cancer growth]. 825 40

Although for centuries plants have been known to have hormone-like actions in humans, the mechanism(s) by which plant-derived compounds act in humans is still being elucidated, a goal that has assumed more importance due to interest in the protective actions of fruits and vegetables in diseases such as cancer. Here I use the "molecular fossil record" of amino acid sequences of proteins involved in regulating the actions steroids, retinoids, thyroid hormone and prostaglandins to propose some mechanisms by which flavonoids in fruits and vegetables can have hormone-like actions in humans. I focus on: i) hormone receptors that bind to DNA and regulate gene transcription and ii) the enzymes that regulate the concentrations of these hormones. Comparative analyses of amino acid sequences show that nuclear receptors for steroids, retinoids, thyroid hormone and prostaglandins in humans and insects are descended from a common ancestor. Similar analyses of dehydrogenases that regulate the concentrations of steroids, retinoids and prostaglandins reveal strong sequence similarity to enzymes in plants, insects, fungi, and bacteria. The similarity is sufficient to suggest that some compounds that bind receptors or enzymes in invertebrates, plants or unicellular organisms may also bind to mammalian homologs that are involved in endocrine physiology. Among the phytochemicals that are candidates for such activity are flavonoids because they are involved in plant-insect and plant-bacteria interactions and have some structural and chemical similarities to steroids, retinoids, thyroid hormone, prostaglandins and fatty acids. These similarities and the kinship of human, plant, insect and bacterial proteins involved in signal transduction provide a conceptual framework for investigating flavonoids for hormone-like actions in humans. Understanding these modes of action may be useful in developing protocols for preventing hormone-dependent diseases such as breast and prostate cancer.
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PMID:Flavonoids as hormones. A perspective from an analysis of molecular fossils. 978 8

Changes in circulating levels of insulin-like growth factors (IGF) and IGF-binding proteins (IGFBP) have been related to prostate cancer, but the nature and the significance of this relationship remains elusive. Recent reports suggest that modulation of the production of IGFBP-3 by retinoids may affect growth of breast and prostate tumor cells. In the present study we explored whether androgens (R1881), retinoids (all-trans- and 9-cis-retinoic acid: atRA and 9cRA), deltanoids (1alpha,25-dihydroxycholecalciferol: VD3) and thyroid hormone (triiodothyronine: T3) influence the production of IGFBPs by LNCaP prostatic adenocarcinoma cells and whether the observed changes affect tumor cell growth. Northern blot experiments demonstrated that LNCaP cells express IGFBP-2, -3, -4 and (to a small extent) -5. IGFBP-4 and -5 were not measurably affected by the mentioned agonists. At a growth promoting concentration (10(-10) M), R1881 increased IGFBP-2 transcript levels two- to three-fold and this effect was neutralized by atRA and VD3. Similar effects could not be demonstrated, however, at the protein level using Western ligand blotting. R1881 decreased and atRA increased the mRNA levels of IGFBP-3 and these effects were confirmed by Western ligand blotting and by radioimmunoassay. The effects of atRA were mimicked by 9cRA and by a specific RAR agonist but not by a RXR agonist. VD3 and T3 had no significant effect on IGFBP-3 secretion but respectively enhanced or decreased the effect of 9cRA. The effects of retinoids required high concentrations (10(-6)-10(-5) M) that also induced growth inhibition. R1881, however, decreased IGFBP-3 at growth promoting (10(-10) M) as well as at growth inhibitory (10(-8) M) concentrations. Moreover, under serum-free conditions, we were unable to demonstrate any growth modulating effect of IGFBP-3. It is concluded that several agonists acting by nuclear receptors affect IGFBP-3 secretion by LNCaP cells but that the functional significance of these changes warrants further investigation.
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PMID:Androgens decrease and retinoids increase the expression of insulin-like growth factor-binding protein-3 in LNcaP prostatic adenocarcinoma cells. 1058 Aug 34

Prostate-specific antigen (PSA) is the most useful biomarker for human prostate cancer and may play a role in prostate tumor biology. Androgens, via their receptors, are the major positive regulators of PSA expression. Recently, we showed that thyroid hormone 3,5,3'-L-triiodothyronine (T3) also increases androgen-dependent PSA expression, even though androgen receptor expression is not affected. This report demonstrates for the first time that there is a functional T3-responsive element (TRE) in the 5'-promoter region of the PSA gene. Mutation of this TRE reduced the T3-enhanced androgenic activation of the PSA promoter. Our study provides direct evidence that the PSA gene is regulated by T3 at the transcriptional level.
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PMID:Androgen-Dependent transcriptional regulation of the prostate-specific antigen gene by thyroid hormone 3,5,3'-L-triiodothyronine. 1119 Oct 79

1alpha,25-Dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)], the active metabolite of vitamin D(3), is known for the maintenance of mineral homeostasis and normal skeletal architecture. However, apart from these traditional calcium-related actions, 1,25-(OH)(2)D(3) and its synthetic analogs are being increasingly recognized for their potent antiproliferative, prodifferentiative, and immunomodulatory activities. These actions of 1,25-(OH)(2)D(3) are mediated through vitamin D receptor (VDR), which belongs to the superfamily of steroid/thyroid hormone nuclear receptors. Physiological and pharmacological actions of 1,25-(OH)(2)D(3) in various systems, along with the detection of VDR in target cells, have indicated potential therapeutic applications of VDR ligands in inflammation (rheumatoid arthritis, psoriatic arthritis), dermatological indications (psoriasis, actinic keratosis, seborrheic dermatitis, photoaging), osteoporosis (postmenopausal and steroid-induced osteoporosis), cancers (prostate, colon, breast, myelodysplasia, leukemia, head and neck squamous cell carcinoma, and basal cell carcinoma), secondary hyperparathyroidism, and autoimmune diseases (systemic lupus erythematosus, type I diabetes, multiple sclerosis, and organ transplantation). As a result, VDR ligands have been developed for the treatment of psoriasis, osteoporosis, and secondary hyperparathyroidism. Furthermore, encouraging results have been obtained with VDR ligands in clinical trials of prostate cancer and hepatocellular carcinoma. This review deals with the molecular aspects of noncalcemic actions of vitamin D analogs that account for the efficacy of VDR ligands in the above-mentioned indications.
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PMID:Noncalcemic actions of vitamin D receptor ligands. 1579 98

Vitamin D receptor (VDR), a member of the steroid/thyroid hormone nuclear receptor family, is bound by the steroid hormone 1,25-dihydroxyvitamin D3, which is thought to play a role in the etiology and progression of prostate cancer. Polymorphisms in the VDR gene have been associated with prostate cancer risk, although findings are inconclusive. The purpose of this study was to determine if VDR polymorphisms were associated with prostate cancer risk using a large, Australian population-based study of 812 cases and 713 controls frequency-matched by age. As the 3' region polymorphisms are in strong linkage disequilibrium, for joint effects, we only evaluated the common g.60890G > A polymorphism with the unlinked g.27823C > T (5' region) polymorphism. Allele frequencies were similar in cases and controls (g.27823C > T, 36% versus 36%; g.60890 G>A, 41% versus 43%). No genotypes were individually associated with prostate cancer risk (all P > 0.3). All nine possible genotype combinations were evident, and although the g.27823CT/g.60890GA combination was nominally more prevalent in controls (24%) than in cases (19%, P = 0.03), there was no difference in the combined genotype distribution between cases and controls (P = 0.2). The associations of risk with genotype were between 0.91 and 1.03, all with 95% confidence intervals within 0.81 to 1.15. In conclusion, VDR polymorphisms either alone or in combination do not seem to contribute appreciably to prostate cancer risk.
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PMID:Genetic variants in the vitamin D receptor gene and prostate cancer risk. 1582 77

Current approaches to inhibit nuclear receptor (NR) activity target the hormone binding pocket but face limitations. We have proposed that inhibitors, which bind to nuclear receptor surfaces that mediate assembly of the receptor's binding partners, might overcome some of these limitations. The androgen receptor (AR) plays a central role in prostate cancer, but conventional inhibitors lose effectiveness as cancer treatments because anti-androgen resistance usually develops. We conducted functional and x-ray screens to identify compounds that bind the AR surface and block binding of coactivators for AR activation function 2 (AF-2). Four compounds that block coactivator binding in solution with IC(50) approximately 50 microM and inhibit AF-2 activity in cells were detected: three nonsteroidal antiinflammatory drugs and the thyroid hormone 3,3',5-triiodothyroacetic acid. Although visualization of compounds at the AR surface reveals weak binding at AF-2, the most potent inhibitors bind preferentially to a previously unknown regulatory surface cleft termed binding function (BF)-3, which is a known target for mutations in prostate cancer and androgen insensitivity syndrome. X-ray structural analysis reveals that 3,3',5-triiodothyroacetic acid binding to BF-3 remodels the adjacent interaction site AF-2 to weaken coactivator binding. Mutation of residues that form BF-3 inhibits AR function and AR AF-2 activity. We propose that BF-3 is a previously unrecognized allosteric regulatory site needed for AR activity in vivo and a possible pharmaceutical target.
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PMID:A surface on the androgen receptor that allosterically regulates coactivator binding. 1791 Dec 42

We cloned a novel splicing variant for nuclear coactivator p120(alpha), designated as p120beta and studied its function and expression in several human prostate diseases. Transfection assays demonstrated that p120beta functions as a strong coactivator for androgen receptor (AR), but weakly for other nuclear receptors. GST-pull down assay showed that a glutamine-rich region of the p120 bound to the ligand-binding domain of AR. Interestingly, p120beta mRNAs were expressed predominantly in the normal prostate, androgen-responsive prostate cancers and an androgen-sensitive prostate cancer cell line, LNCaP, but weakly in recurrent cancers and the androgen-insensitive prostate cancer cell lines PC3 and DU145. Furthermore, knockdown of p120alpha by siRNA abolished coactivator activity on thyroid hormone receptors (TR) and PPARgamma, but did not affect that of ARs in PC3 cells. In addition, competitive assay with other nuclear receptors demonstrated that TR and PPARgamma did not inhibit p120beta-induced stimulation. These findings suggested that while p120alpha was essential for ligand-dependent stimulation of TRs and PPARgamma, p120beta acted as a coactivating protein predominantly for AR.
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PMID:A novel splice variant of the nuclear coactivator p120 functions strongly for androgen receptor: characteristic expression in prostate disease. 1856 Feb 2


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