Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:Q7LGC8 (HSD)
 3,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Isoflavones and others phytoestrogens have been suggested to be anticarcinogenic. Anti-aromatase, antiestrogenic or antiproliferative actions of these compounds have been postulated and related to the observation that there is a reduced incidence of breast cancer associated with diet. In this study, we explored some mechanisms by which they can exert cancer-preventive effects. Phytoestrogens were tested for estimating anti-aromatase, anti-3beta-hydroxysteroid dehydrogenase delta5/delta4 isomerase (3beta-HSD) and anti-17beta-hydroxysteroid dehydrogenase (17beta-HSD) activities in human placental microsomes. We found that isoflavonoids and compounds which presented the phenolic B ring in the 3 position on the pyran ring preferentially inhibited 3beta-HSD and/or 17beta-HSD activities than aromatase activity. We also evaluated their interactions with the estrogen receptor using a stably transfected human breast cancer cell line (MVLN). On the other hand phytoestrogens were evaluated for their effects on the proliferation in estrogen-dependent (MCF-7) and independent (MDA-MB231) human breast cancer cells. We established a relationship structure-activity and determined regions or/and substituents essential for these different activities. However, at high concentrations it seems that some phytoestrogens exert their protection against breast cancer through other estrogen-independent mechanisms.
 ...
PMID:Effects of phytoestrogens on aromatase, 3beta and 17beta-hydroxysteroid dehydrogenase activities and human breast cancer cells. 1075 63

The 3beta-hydroxysteroid dehydrogenase/Delta5-Delta4 isomerase (3beta-HSD) isoenzymes catalyze an essential step in the formation of all classes of active steroid hormones. We have recently shown that 3beta-HSD type 1 gene expression is specifically induced by interleukin (IL)-4 and IL-13 in several human cancer cell lines and in normal human mammary and prostatic epithelial cells in primary culture. There is evidence that IL-4 stimulates bifurcating signaling pathways in which the Stat6-signal pathway is involved in differentiation and gene regulation, whereas insulin receptor substrate (IRS) proteins mediate the mitogenic action of IL-4. As a matter of fact, we have shown that IL-4-activated Stat6 in all cell lines studied, where IL-4 induced 3beta-HSD type 1 expression but not in those cell lines that failed to respond to IL-4. The mechanism of the induction of 3beta-HSD type 1 gene expression was further characterized in ZR-75-1 human breast cancer cells. We have also found that IL-4 rapidly induced IRS-1 and IRS-2 phosphorylation in these cell lines. Moreover, insulin-like growth factor (IGF)-1 and insulin, which are well known to cause IRS-1 and IRS-2 phosphorylation, increased the stimulatory effect of IL-4 on 3beta-HSD activity. IRS-1 and IRS-2 are adapter molecules that provide docking sites for different SH2 domain-containing proteins, leading to the activation of multiple pathways, such as the phosphatidylinositol (PI) 3-kinase and the mitogen-activated protein (MAP) pathways. The inhibition of IL-4-induced 3beta-HSD expression by PI 3-kinase inhibitors (wortmannin and LY294002) as well as an inhibitor of MAP kinase activation (PD98059), indicates the involvement of those pathways in this response to IL-4. Wortmannin also blocked MAP kinase activation by IL-4, insulin and IGF-1 suggesting that the MAP kinase cascade acts as a downstream effector of PI 3-kinases. Furthermore, we showed that the PKC activator phorbol-12-myristate-13-acetate (PMA) also potentiated the IL-4-induced 3beta-HSD activity, thus suggesting that one signaling molecule that is involved in the signal transduction of the IL-4 action on 3beta-HSD type 1 expression is also a substrate for PKC. Taken together, these findings suggest the existence of a novel mechanism of gene regulation by IL-4. This mechanism would involve in the phosphorylation of IRS-1 and IRS-2, which transduce the IL-4 signal through a PI 3-kinase- and MAP kinase-dependent signaling pathway. However, the inability of IGF-1, insulin and PMA to stimulate 3beta-HSD type 1 expression by themselves in the absence of IL-4 indicates that the multiple pathways downstream of IRS-1 and IRS-2 must act in cooperation with an IL-4-specific signaling molecule, such as the transcription factor Stat6. It is also of interest to note that there also appear to be differences between the regulation of the 3beta-HSD type 1 and type 2 promoters.
 ...
PMID:Multiple signal transduction pathways mediate interleukin-4-induced 3beta-hydroxysteroid dehydrogenase/Delta5-Delta4 isomerase in normal and tumoral target tissues. 1138 80

17 beta-hydroxysteroid dehydrogenases catalyze the oxidoreduction of hydroxy/oxo groups at position C17 of steroid hormones, thereby constituting a prereceptor control mechanism of hormone action. At present, 11 different mammalian 17 beta-hydroxysteroid dehydrogenases have been identified, catalyzing the cell- and steroid-specific activation and inactivation of estrogens and androgens. The human type 10 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD-10) is a multifunctional mitochondrial enzyme that efficiently catalyzes the oxidative inactivation at C17 of androgens and estrogens. However, it also mediates oxidation of 3 alpha-hydroxy groups of androgens, thereby reactivating androgen metabolites. Finally, it is involved in beta-oxidation of fatty acids by catalyzing the L-hydroxyacyl CoA dehydrogenase reaction of the beta-oxidation cycle. These features and expression profiles suggest a critical role of 17 beta-HSD-10 in neurodegenerative and steroid-dependent cancer forms. Since no three-dimensional structure of 17 beta-HSD-10 is available, homology modelling was carried out to understand the molecular basis of these substrate specificities. The structure obtained displays the properties of a one-domain, alpha/beta fold enzyme of the SDR family. The active site is located within a large, hydrophobic cleft, which forms optimal contacts with the different steroid surfaces. The data provide explanations for the substrate specificities toward the various classes of sex steroid hormones. The model is suitable to explore substrate and inhibitor characteristics that may be used in the development of novel strategies in the treatment of degenerative or malignant diseases.
 ...
PMID:Human type 10 17 beta-hydroxysteroid dehydrogenase: molecular modelling and substrate docking. 1155 79

Inherent or acquired resistance of tumor cells to anti-cancer drugs is a problem of major importance in chemotherapy. In addition to detailed research into the mechanisms of drug inactivation, attention has also been paid to the synthesis of new structures. Oracin is a promising cytostatic drug, which is presently in phase II of clinical trials. This investigation was designed to characterize the metabolic inactivation of oracin by carbonyl reduction to 11-dihydrooracin (DHO). We identified 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD 1) as the principal enzyme being responsible for oracin carbonyl reduction in human liver microsomes. The purified 11beta-HSD 1 catalyses this reaction in a stereospecific manner. Formation of (-)-DHO surpasses that of (+)-DHO by a factor of around four. Moreover, 11beta-HSD 1 exhibits enzyme cooperativity for the formation of both enantiomers (Hill coefficients of 2.26 +/- 0.20 and 1.84 +/- 0.29 for (-)-DHO and (+)-DHO, respectively). Comparing the differences in the stereospecificity and Hill coefficients between the microsomes and purified 11beta-HSD 1 could anticipate contribution of another microsomal enzyme. In case of oracin, this enzyme cooperativity may become important with respect to maximal plasma concentrations, and, by inhibition of 11beta-HSD 1, to enhance the chemotherapeutic efficacy of this anti-cancer drug.
 ...
PMID:The novel anticancer drug oracin: different stereospecificity and cooperativity for carbonyl reduction by purified human liver 11beta-hydroxysteroid dehydrogenase type 1. 1503 47

To verify the relevance of 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) activity in controlling breast-cancer cell growth, we have evaluated the correlation of 11beta-HSD2 expression and antiproliferative effects of glucocorticosteroids (GCs) on breast cancer cell proliferation. We cloned human 11beta-HSD2 cDNA into the expression vector pBK-CMV. The interspersing lac promoter region was deleted, achieving differential translational efficiency. The constructs were stably transfected into wild-type MCF-7 breast-cancer cells possessing almost no oxidative and no reductive 11beta-HSD activity. Low (times 7) and high (times 718) 11beta-HSD2 overexpression was achieved. We compared growth behavior of transfected cells In the presence of GCs to MCF-7 cells transfected with pBK-CMV alone (internal control). The antiproliferative effects of GCs were reversed and total cell growth boosted by overexpression of 11beta-HSD2; about 50 % of the increase in cell proliferation was attained by low 11beta-HSD2 overexpression, while high enzyme overexpression led to an increase in cell growth of about 120 %. Using direct evidence, this study shows 11beta-HSD2 to impair antiproliferative glucocorticosteroid effects, thus acting as an enzymatic shield aggravating breast-cancer cell growth. These results indicate a possible therapeutic role for 11beta-HSD inhibitors in the treatment of breast cancer.
 ...
PMID:Impairment of the antiproliferative effect of glucocorticosteroids by 11beta-hydroxysteroid dehydrogenase type 2 overexpression in MCF-7 breast-cancer cells. 1530 25

Steroidogenic acute regulatory protein (StAR), P450 side-chain cleavage enzyme (P450scc) and 3 beta-hydroxysteroid dehydrogenase enzyme (3beta-HSD) are all involved in the transport of cholesterol and production of progesterone. In situ production of sex steroids including progesterone have been considered to play important roles in pathogenesis and/or development of common epithelial ovarian carcinomas. In this study, StAR, P450scc, and 3beta-HSD were immunolocalized in 100 cases of ovarian carcinoma and results were then correlated with clinicopathological and prognostic parameters of individual patients including status of progesterone receptor (PR) in tumor cells. Results of immunohistochemistry were further characterized by real-time PCR analysis in 20 cases of epithelial ovarian carcinomas in which frozen tissues were available for examination. StAR, P450scc, and 3beta-HSD immunoreactivity was detected predominately in the cytoplasm of carcinoma cells. Results of real-time PCR analysis were correlated with those of immunohistochemical studies. StAR, P450scc, and 3beta-HSD H scores demonstrated significant inversed statistical correlation with FIGO stage, residual size of the tumor, and Ki67 LI. A positive statistically significant correlation was detected between StAR H score and PR-B LI. Multivariate statistical analysis demonstrated that the status of intratumoral StAR, FIGO stage, and residual tumor size all turned out to be independent prognostic factors for the clinical outcome of the patient. The presence of StAR, a cholesterol transporter for steroidogenesis in human epithelial ovarian carcinoma, may reflect the ability of these tumors to produce progesterone in situ that could influence biological behavior of these tumors, especially through progesterone dependent inhibition of tumor cell proliferation.
Cancer Sci 2005 Apr
PMID:StAR and progesterone producing enzymes (3beta-hydroxysteroid dehydrogenase and cholesterol side-chain cleavage cytochromes P450) in human epithelial ovarian carcinoma: immunohistochemical and real-time PCR studies. 1581 22

In the ovary cortisol-cortisone inter-conversion is catalyzed by the enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD). Its role in carcinomas of human ovary is unknown. The majority of ovarian cancers are derived from ovarian surface epithelium and the inflammation caused by successive ovulation seems to a play a role in the development of cancer. Cortisol is known to act as anti-inflammatory agent and its metabolism by type 1 and type 11beta-HSD may control the inflammatory action by cortisol in ovary. We undertook this study to investigate type 2 11beta-HSD activity which functions exclusively oxidative direction, in normal ovarian tissue compared to ovarian epithelial cancer. Ovarian tissue was obtained from patients undergoing hysterectomy for both benign and malignant disease. Tissue was placed immediately on dry ice and subsequently transferred to a freezer where they were maintained at -70 degrees C. NAD dependent 11beta-HSD activity was then determined in this tissue. T-test was performed to determine statistical significance. Mean type 2 enzyme activity was 0.87 +/- 1.65 pmol/min g tissue in normal ovarian tissue versus a mean enzyme activity of 2.96 +/- 1.37 pmol/mim g tissue in from cancer specimens. This difference was statistically significant with a p-value of 0.03. Type 2 1beta-HSD activity in ovarian cancer specimens was significantly higher than enzyme activity measured in normal post-menopausal ovarian tissue. Decreased cortisol levels due type 2 1beta-HSD activity may play a role neoplastic transformation as well as tumor proliferation in ovarian cancer by eliminating anti-inflammatory action of cortisol.
 ...
PMID:Type 2 11beta-hydroxysteroid dehydrogenase activity in human ovarian cancer. 1702 49

Breast carcinomas are characterized by DNA copy number alterations (CNAs) with biological and clinical significance. This explorative study integrated CNA, expression, and germline genotype data of 112 early-stage breast cancer patients. Recurrent CNAs differed substantially between tumor subtypes classified according to expression pattern. Deletion of 16q was overrepresented in Luminal A, and a predictor of good prognosis, both overall and for the nonluminal A subgroups. The deleted region most significantly associated with survival mapped to 16q22.2, harboring the genes TXNL4B and DXH38, whose expression was strongly correlated with the deletion. The area most frequently deleted resided on 16q23.1, 3.5 MB downstream of the area most significantly associated with survival, and included the tumor suppressor gene ADAMTS18 and the cell recognition gene CNTNAP4. Whole-genome association analysis identified germline single nucleotide polymorphisms (SNPs) and their corresponding haplotypes, residing on several different chromosomes, to be associated with deletion of 16q. The genes where these SNPs reside encode proteins involved in the extracellular matrix (CHST3 and SPOCK2), in regulation of the cell cycle (JMY, PTPRN2, and Cwf19L2) and chromosome stability (KPNB1).
Genes Chromosomes Cancer 2008 Aug
PMID:Genome-wide analysis identifies 16q deletion associated with survival, molecular subtypes, mRNA expression, and germline haplotypes in breast cancer patients. 1839 21

17beta-Hydroxysteroid dehydrogenases (17beta-HSDs) are enzymes that are responsible for reduction or oxidation of hormones, fatty acids and bile acids in vivo, regulating the amount of the active form that is available to bind to its cognate receptor. All require NAD(P)(H) for activity. Fifteen 17beta-HSDs have been identified to date, and with one exception, 17beta-HSD type 5 (17beta-HSD5), an aldo-keto reductase, they are all short-chain dehydrogenases/reductases, although overall homology between the enzymes is low. Although named as 17beta-HSDs, reflecting the major redox activity at the 17beta-position of the steroid, the activities of these 15 enzymes vary, with several of the 17beta-HSDs able to reduce and/or oxidise multiple substrates at various positions. These activities are involved in the progression of a number of diseases, including those related to steroid metabolism. Despite the success of inhibitors of steroidogenic enzymes in the clinic, such as those of aromatase and steroid sulphatase, the development of inhibitors of 17beta-HSDs is at a relatively early stage, as at present none have yet reached clinical trials. However, many groups are now working on inhibitors specific for several of these enzymes for the treatment of steroid-dependent diseases, including breast and prostate cancer, and endometriosis, with demonstrable efficacy in in vivo disease models. In this review, the recent advances in the validation of these enzymes as targets for the treatment of these diseases, with emphasis on 17beta-HSD1, 3 and 5, the development of specific inhibitors, the models used for their evaluation, and their progress towards the clinic will be discussed.
Endocr Relat Cancer 2008 Sep
PMID:Design and validation of specific inhibitors of 17beta-hydroxysteroid dehydrogenases for therapeutic application in breast and prostate cancer, and in endometriosis. 1854 21

17beta-Hydroxysteroid dehydrogenases (17beta-HSDs) are responsible for the pre-receptor reduction/oxidation of steroids at the 17-position into active/inactive hormones, and the 15 known enzymes vary in their substrate specificity, localisation, and directional activity. 17beta-HSD Type 3 (17beta-HSD3) has been seen to be over-expressed in prostate cancer, and catalyses the reduction of androstenedione (Adione) to testosterone (T), which stimulates prostate tumour growth. Specific inhibitors of 17beta-HSD3 may have a role in the treatment of hormone-dependent prostate cancer and benign prostate hyperplasia, and also have potential as male anti-fertility agents. A 293-EBNA-based cell line with stable expression of transfected human 17beta-HSD3 was created and used to develop a whole cell radiometric TLC-based assay to assess the 17beta-HSD3 inhibitory potency of a series of compounds. STX2171 and STX2624 (IC(50) values in the 200-450nM range) were two of several active inhibitors identified. In similar TLC-based assays these compounds were found to be inactive against 17beta-HSD1 and 17beta-HSD2, indicating selectivity. A novel proof of concept model was developed to study the efficacy of the compounds in vitro using the androgen receptor positive hormone-dependent prostate cancer cell line, LNCaPwt, and its derivative, LNCaP[17beta-HSD3], transfected and selected for stable expression of 17beta-HSD3. The proliferation of the parental cell line was most efficiently stimulated by 5alpha-dihydrotestosterone (DHT), but the LNCaP[17beta-HSD3] cells were equally stimulated by Adione, indicating that 17beta-HSD3 efficiently converts Adione to T in this model. Adione-stimulated proliferation of LNCaP[17beta-HSD3] cells was inhibited in the presence of either STX2171 or STX2624. The compounds alone neither stimulated proliferation of the cells nor caused significant cell death, indicating that they are non-androgenic with low cytotoxicity. STX2171 inhibited Adione-stimulated growth of xenografts established from LNCaPwt cells in castrated mice in vivo. In conclusion, a primary screening assay and proof of concept model have been developed to study the efficacy of 17beta-HSD3 inhibitory compounds, which may have a role in the treatment of hormone-dependent cancer. Active compounds are selective for 17beta-HSD3 over 17beta-HSD1 and 17beta-HSD2, non-androgenic with low toxicity, and efficacious in both an in vitro proof of concept model and in an in vivo tumour model.
 ...
PMID:Development of hormone-dependent prostate cancer models for the evaluation of inhibitors of 17beta-hydroxysteroid dehydrogenase type 3. 1878 4


<< Previous 1 2 3 4 5 6 7 Next >>