Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.6.1 (sulfatase)
3,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The involvement of aromatase, steroid sulfatase (STS) and reductive 17beta-hydroxysteroid dehydrogenases (17beta-HSDs) in the production of estrogens was determined in four cell lines of endometrial cancer (Ishikawa, HEC-1A, HEC-1B and RL-95) and one cell line of cervix cancer (Hela) in culture. After incubation with 4-androstene-3,17-dione (4-dione), there are no estrogens, estrone (E1) and estradiol (E2), detected suggesting that the pathway of aromatase is not important in these cell lines. In whole cells, the results show low percentages of transformation of estrone sulfate (E1S) into E1 suggesting that the entrance of E1S is difficult. However, in homogenized cells the STS activity was much higher and fully blocked by an inhibitor. Using selective inhibitors for each reductive 17beta-HSD (types 1, 5, 7 and 12), alone or in combination, we did not succeed in completely blocking the conversion of E1 into E2, suggesting that another 17beta-HSD (known or unknown) is involved in the formation of E2 from E1.
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PMID:Estrogen formation in endometrial and cervix cancer cell lines: involvement of aromatase, steroid sulfatase and 17beta-hydroxysteroid dehydrogenases (types 1, 5, 7 and 12). 1881 41

Endometrial cancer is related to estrogen stimulation not opposed by progesterone. We have examined expression of the pre-receptor regulatory enzymes aromatase, 17beta-hydroxysteroid dehydrogenases (17beta-HSDs), 20alpha-hydroxysteroid dehydrogenases (20alpha-HSDs), sulfatase and sulfotransferase, and estrogen (ERs) and progesterone (PRs) receptors in samples of endometrial cancer and adjacent normal endometrium. No significant gene up-regulation was seen, although aromatase, AKR1C3, a 17beta-HSD and 20alpha-HSD, and AKR1C1, the major 20alpha-HSD, were up-regulated in 50% of samples. Significant down-regulation was seen for 17beta-HSD types 1 and 7, sulfotransferase, ERalpha, ERbeta, PR-AB. Western blotting revealed higher levels of AKR1C3 and PR-B and lower levels of ERalpha in cancerous endometrium, and immunohistochemistry confirmed expression of AKR1C3, PR-B and ERalpha at the cellular level. Up-regulation of aromatase in concert with AKR1C3 can lead to increased levels of estradiol, which acts via ERalpha. Up-regulation of AKR1C1 and AKR1C3 can result in lower levels of the protective progesterone, which acts mainly via PR-B.
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PMID:Aberrant pre-receptor regulation of estrogen and progesterone action in endometrial cancer. 1893 Jul 84

The coumarin (benzopyran-2-one, or chromen-2-one) ring system, present in natural products (such as the anticoagulant warfarin) that display interesting pharmacological properties, has intrigued chemists and medicinal chemists for decades to explore the natural coumarins or synthetic analogs for their applicability as drugs. Many molecules based on the coumarin ring system have been synthesized utilizing innovative synthetic techniques. The diversity oriented synthetic routes have led to interesting derivatives including the furanocoumarins, pyranocoumarins, and coumarin sulfamates (COUMATES), which have been found to be useful in photochemotherapy, antitumor and anti-HIV therapy, and as stimulants for central nervous system, antibacterials, anti-inflammatory, anti-coagulants, and dyes. Of particular interest in breast cancer chemotherapy, some coumarins and their active metabolite 7-hydroxycoumarin analogs have shown sulfatase and aromatase inhibitory activities. Coumarin based selective estrogen receptor modulators (SERMs) and coumarin-estrogen conjugates have also been described as potential antibreast cancer agents. Since breast cancer is the second leading cause of death in American women behind lung cancer, there is a strong impetus to identify potential new drug treatments for breast cancer. Therefore, the objective of this review is to focus on important coumarin analogs with antibreast cancer activities, highlight their mechanisms of action and structure-activity relationships on selected receptors in breast tissues, and the different methods that have been applied in the construction of these pharmacologically important coumarin analogs.
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PMID:A review of coumarin derivatives in pharmacotherapy of breast cancer. 1899 29

Estrogen action is regulated at the receptor level by regulation of expression of estrogen receptors, and at the pre-receptor level by interconversions between the active hormone (estradiol) and its inactive counterparts (estrone, estrone-sulfate). In peripheral tissues, estrogens can be produced via the aromatase or the sulfatase pathways. Aromatase converts androstenedione and testosterone to estrone and estradiol, respectively, and sulfatase releases estrogens from inactive sulfates, while sulfotransferase catalyzes the reverse reaction. In both pathways, 17beta-hydroxysteroid dehydrogenases (17beta-HSDs) are of paramount importance as they catalyze activation of estrone to estradiol and inactivation of estradiol to estrone. These enzymes belong to either the short-chain dehydrogenase/reductase (SDR) or the aldo-keto reductase (AKR) protein superfamilies. Differential expression of these pre-receptor regulatory enzymes can lead to high estradiol concentrations, which have been implicated in the development of different diseases. Here, we have examined gene expression levels of estrogen-metabolizing enzymes, as six SDRs (17beta-HSD types 1, 2, 4, 7, 8, 12) and one AKR (17beta-HSD type 5; AKR1C3), of aromatase, steroid sulfatase (STS) and estrogen sulfotransferase (SULT1E1), and of the alpha and beta estrogen receptors (ERs), in breast cancer (MCF-7), endometrial cancer (Ishikawa), choriocarcinoma (JEG3) and liver cancer (HepG2) cell lines. After RNA isolation and cDNA synthesis, real-time PCR analyses were performed. The expression of AKR1C3 was examined also at the protein level. Our data show that in all four cancer cell lines, estradiol can be synthesized from estrone by the action of 17beta-HSD type 12, or from estrone-sulfate by sulfatase. In JEG3 and HepG2 cells, estradiol can be formed from androgens by aromatase and 17beta-HSD type 1. Also in HepG2 cells, AKR1C3, which converts androstenedione to testosterone, in concert with aromatase might be responsible for estradiol formation. In MCF7 and Ishikawa cells, estradiol exerts its actions through ERalpha, while in JEG3 and HepG2 cells, it may act through non-ER-mediated pathways.
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PMID:Expression of 17beta-hydroxysteroid dehydrogenases and other estrogen-metabolizing enzymes in different cancer cell lines. 1902 35

Estradiol, the most potent estrogen, plays critical roles in tumor cell proliferation and breast cancer development. It can be synthesized via the aromatase pathway or the sulfatase pathway, and the later has been demonstrated to be more significant. Reductive 17beta-hydroxysteroid dehydrogenases (17beta-HSDs) catalyze the last step in estrogen activation and are thus critical in breast cancer development. 17beta-HSD Type 1 (17beta-HSD1) is of great importance since it efficiently synthesizes the most potent estrogen estradiol, as well as other estrogens as 5-androstene-3beta,17beta-diol and 5alpha-androstane-3beta,17beta-diol, and inactivates the most active androgen dihydrotestosterone (DHT), all contributing to the stimulation and development of breast cancers. Rational inhibitor design based on the new structure information has been developed, yielding interesting compounds and lead chemicals. This was demonstrated by a hybrid inhibitor that interacts with both the substrate and cofactor binding sites and a recently designed inhibitor 3-(3',17'beta-dihydroxyestra-1',3',5'(10')-trien-16'beta-methyl) benzamide which has been crystallized in complex with 17beta-HSD1. Both inhibitors demonstrate nM level K(i)in vitro. New non-steroidal inhibitors have been designed and reported very recently. The Type 7 17beta-HSD, expressed in several tissues including breast and ovary, can also contribute to estrogen synthesis and DHT inactivation in breast cancer cells. The enzyme role in steroid metabolism and cancer cell proliferation needs to be compared to that in cholesterogenesis. Breast cancer cell lines provide an excellent platform for such study. T47D, MCF-7 and MDA-MB-231-luc cells have been used to create xenografts in nude mice as animal models, now with the possibility of bioluminescent imaging to provide rapid, non-invasive, and quantitative analysis of tumor biomass and metastasis. Here we review the roles of the sulfatase and aromatase pathways and the contribution of the reductive 17beta-HSDs for hormone metabolism in breast cancer.
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PMID:Reductive 17beta-hydroxysteroid dehydrogenases in the sulfatase pathway: critical in the cell proliferation of breast cancer. 1903 8

Melatonin exerts oncostatic effects on different kinds of tumors, especially on hormone-dependent breast cancer. The general conclusion is that melatonin, in vivo, reduces the incidence and growth of chemically-induced mammary tumors in rodents, and, in vitro, inhibits the proliferation and invasiveness of human breast cancer cells. Both studies support the hypothesis that melatonin inhibits the growth of breast cancer by interacting with estrogen-signaling pathways through three different mechanisms: (a) the indirect neuroendocrine mechanism which includes the melatonin down-regulation of the hypothalamic-pituitary-reproductive axis and the consequent reduction of circulating levels of gonadal estrogens, (b) direct melatonin actions at tumor cell level by interacting with the activation of the estrogen receptor, thus behaving as a selective estrogen receptor modulator (SERM), and (c) the regulation of the enzymes involved in the biosynthesis of estrogens in peripheral tissues, thus behaving as a selective estrogen enzyme modulator (SEEM). As melatonin reduces the activity and expression of aromatase, sulfatase and 17beta-hydroxysteroid dehydrogenase and increases the activity and expression of estrogen sulfotransferase, it may protect mammary tissue from excessive estrogenic effects. Thus, a single molecule has both SERM and SEEM properties, one of the main objectives desired for the breast antitumoral drugs. Since the inhibition of enzymes involved in the biosynthesis of estrogens is currently one of the first therapeutic strategies used against the growth of breast cancer, melatonin modulation of different enzymes involved in the synthesis of steroid hormones makes, collectively, this indolamine an interesting anticancer drug in the prevention and treatment of estrogen-dependent mammary tumors.
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PMID:Melatonin as a selective estrogen enzyme modulator. 1907 92

It is well documented that human breast is actively involved in the local formation of estrogens. To determine the site(s) of action of enzymes involved in synthesis and metabolism of the most potent estrogen estradiol (E2), we have studied the expression of the following enzymes: 3beta-hydroxysteroid dehydrogenase (3-HSD), 17beta-HSD types 1, 2, 5, 7 and 12, aromatase, steroid sulfatase (STS) and estrogen sulfotransferase (EST) 1E1 at the cellular level in breast. Both in situ hybridization and immunocytochemistry were used for enzyme localization in normal breast tissues. For immunocytochemistry, we used rabbit antibodies, while in situ hybridization studies were performed using (35S)-labeled cRNA probes. Similar results were obtained with both approaches. All the enzymes (3beta-HSD; 17beta-HSD types 1, 5, 7 and 12; aromatase) involved in the conversion of circulating dehydroepiandrosterone (DHEA) to E2 as well as STS which converts estradiol sulfate (E2-S) to E2 have been found to be expressed in epithelial cells of acini and/or ducts as well as the stromal cells. Moreover, 17beta-HSD type 2 and EST1E1, two enzymes which inactivate E2, have been also localized in the same cell types. The present results indicate the enzymes which play a role in the synthesis and metabolism of E2 are expressed in both epithelial and stromal cells in human breast.
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PMID:Expression of enzymes involved in synthesis and metabolism of estradiol in human breast as studied by immunocytochemistry and in situ hybridization. 1913 Mar 96

Previous epidemiologic and in vitro studies have indicated a potential involvement of estrogens in the pathogenesis of human colon carcinoma, but the precise roles of estrogens have remained largely unknown. Therefore, in this study, we first measured intratumoral concentrations of estrogens in 53 colon carcinomas using liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS). Tissue concentrations of total estrogen [estrone (E(1)) + estradiol] and E(1) were significantly (2.0- and 2.4-fold, respectively) higher in colon carcinoma tissues than in nonneoplastic colonic mucosa (n = 31), and higher intratumoral concentrations of total estrogen and E(1) were significantly associated with adverse clinical outcome. Intratumoral concentration of total estrogen was significantly associated with the combined status of steroid sulfatase (STS) and estrogen sulfotransferase (EST), but not with that of aromatase. Thus, we subsequently examined the STS/EST status in 328 colon carcinomas using immunohistochemistry. Immunoreactivities for STS and EST were detected in 61% and 44% of the cases, respectively. The -/+ group of the STS/EST status was inversely associated with Dukes' stage, depth of invasion, lymph node metastasis, and distant metastasis and positively correlated with Ki-67 labeling index of the carcinomas. In addition, this -/+ group had significantly longer survival, and a multivariate analysis revealed the STS/EST status as an independent prognostic factor. Results from our present study showed that the STS/EST status of carcinoma tissue determined intratumoral estrogen levels and could be a significant prognostic factor in colon carcinoma, suggesting that estrogens are locally produced mainly through the sulfatase pathway and play important roles in the progression of the disease.
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PMID:Steroid sulfatase and estrogen sulfotransferase in colon carcinoma: regulators of intratumoral estrogen concentrations and potent prognostic factors. 1914 51

In order to evaluate the importance of estrogen production in tumor and surrounding tissues, we measured mRNA expression levels of 5 enzymes participating to estrogen synthesis in situ and 4 breast cancer-related proteins in 27 pairs of tumor and non-malignant tissues. Steroid sulfatase (STS) mRNA was more frequently detected in tumor tissues rather than in their non-malignant counterparts. Estrogen sulfotransferase (EST) was constantly expressed with high level not only in tumor tissues but also in their surrounding non-malignant counterparts. In contrast, mRNA expression levels of aromatase, and 17beta-hydroxysteroid dehydrogenase type I and II were relatively low and detected only in small proportion of the patients. We also measured the mRNA expression levels of the same nine genes in tumor tissues of 197 breast cancer patients, and analyzed relationship between the mRNA expression level and the clinicopathological parameters. The mRNA expression levels of STS, aromatase and erbB2 in tumor tissues increased as breast cancer progressed. The tumoral mRNA expression levels of STS, estrogen receptor beta, and erbB2 in patients with recurrence were higher than those in patients without recurrence. Upregulation of STS expression plays an important role in tumor progression of human breast cancer and is considered to be responsible for estrogen production in tumor and surrounding tissues.
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PMID:Expression level of enzymes related to in situ estrogen synthesis and clinicopathological parameters in breast cancer patients. 1915 87

The absolute configuration of a newly designed, letrozole-based chiral aromatase inhibitor that could not be defined by crystallographic techniques has been determined by means of vibrational and electronic circular dichroism and by optical rotation measurements combined with density functional theory calculations on possible conformers. The same absolute configurational assignment can be applied to the individual enantiomeric sulfamate esters, which are derived from the corresponding enantiomers of the chirally separated parent phenols, based on the similarity of the ECD spectrum of the sulfamate derivative to that of its phenolic precursor. The two enantiomeric sulfamate esters studied here are the first examples of nonsteroidal dual aromatase-sulfatase inhibitor whose activities have been evaluated on optically resolved enantiomers.
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PMID:Determination of the absolute configuration of aromatase and dual aromatase-sulfatase inhibitors by vibrational and electronic circular dichroism spectra analysis. 1916 Dec 17


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