UMLS:C0376358 - FACTA Search

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Query: UMLS:C0376358 (prostate cancer)
59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been suggested that the activity of the steroid 5alpha-reductase type II enzyme (encoded by the SRD5A2 gene) may be associated with prostate cancer risk and that population differences in this enzyme's activity may account for part of the substantial racial/ethnic disparity in prostate cancer risk. To provide etiological clues, we evaluated the relationships of four polymorphic markers in the SRD5A2 gene, specifically, A49T (a substitution of threonine for alanine at codon 49), V89L (a substitution of leucine for valine at codon 89), R227Q (a substitution of glutamine for arginine at codon 227), and a (TA)n dinucleotide repeat, with prostate cancer risk in a population-based case-control study in China, a population with the lowest reported prostate cancer incidence rate in the world. Genotypes of these four markers were determined from genomic DNA of 191 incident cases of prostate cancer and 304 healthy controls using PCR-based assays, and serum androgen levels were measured in relation to these genotypes. All study subjects had the wild-type AA genotype of the A49T marker, and 99% had the RR genotype of the R227Q marker. For the V89L marker, prevalences of the LL, VV, and VL genotypes among controls were 35%, 21%, and 45%, respectively. Compared with men with the VV genotype, those with the LL genotype had a statistically nonsignificant 12% reduced risk (odds ratio = 0.88, 95% confidence interval, 0.53-1.47). In addition, men with the LL genotype had significantly higher serum levels of testosterone and significantly lower serum levels of 5alpha-androstane-3alpha,17beta-diol glucuronide than men with other genotypes. Men heterozygous for the (TA)0 allele of the (TA)n marker had a modest, statistically nonsignificant risk reduction (odds ratio = 0.67; 95% confidence interval, 0.39-1.12) compared with men homozygous for the (TA)0 allele, along with significantly higher serum dihydrotestosterone levels. The observed V89L genotype prevalences and the association between V89L genotypes and serum androgen levels support the hypothesis that genotypes associated with lower levels of 5alpha-reductase activity are more common in low-risk populations. Although we found no statistically significant associations of these SRD5A2 polymorphisms with prostate cancer risk, a small effect of these markers cannot be ruled out because of the rarity of certain marker genotypes. Larger studies are needed to further clarify the role of these markers and to elucidate whether genetic diversity of the SRD5A2 gene, alone or in combination with other susceptibility genes, can help explain the large racial/ethnic differences in prostate cancer risk.
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PMID:Polymorphic markers in the SRD5A2 gene and prostate cancer risk: a population-based case-control study. 1158 34

17beta-Hydroxysteroid dehydrogenases (17HSDs) have a central role in the regulation of the biological activity of sex steroid hormones. There is increasing evidence that in addition to their importance in gonads, these hormones also have substantial metabolic roles in a variety of peripheral tissues. In the present study, the cDNA of human 17HSD type 7 was cloned. In silico, the gene corresponding to the cDNA was localized on chromosome 1q23, close to the locus of hereditary prostate cancer 1 (HPC1) (1q24-25) and primary open-angle glaucoma (GLC1A) (1q23-25). Further, a pseudogene was found on chromosome 1q44, close to the locus of predisposing for early-onset prostate cancer (PCaP) (1q42.2-43). Both human (h17HSD7) and mouse 17HSD type 7 (m17HSD7) were for the first time produced as recombinant proteins and purified for functional analyses. Further, kinetic parameters and specific activities were described. h17HSD7 converted estrone (E1) to a more potent estrogen, estradiol (E2), and dihydrotestosterone (DHT), a potent androgen, to an estrogenic metabolite 5alpha-androstane-3beta, 17beta-diol (3betaA-diol) equally, thereby catalyzing the reduction of the keto group in either 17- or 3-position of the substrate. Minor 3betaHSD-like activity towards progesterone (P) and 20-hydroxyprogesterone (20-OH-P), leading to the inactivation of P by h17HSD7, was also detected. m17HSD7 efficiently catalyzed the reaction from E1 to E2 and moderately converted DHT to an inactive metabolite 5alpha-androstane-3alpha,17beta-diol (3alphaA-diol) and to an even lesser degree 3betaA-diol. The mouse enzyme did not metabolize P or 20-OH-P. The expression of 17HSD type 7 was observed widely in human tissues, most distinctly in adrenal gland, liver, lung, and thymus. Based on the enzymatic characteristics and tissue distribution, we conclude that h17HSD7 might be an intracrine regulator of steroid metabolism, fortifying the estrogenic milieu in peripheral tissues.
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PMID:Production, purification, and functional analysis of recombinant human and mouse 17beta-hydroxysteroid dehydrogenase type 7. 1273 93

In vitro enzyme assays have demonstrated that human type 10 17beta-hydroxysteroid dehydrogenase (17beta-HSD10) catalyzes the oxidation of 5alpha-androstane-3alpha,17beta-diol (adiol), an almost inactive androgen, to dihydrotestosterone (DHT) rather than androsterone or androstanedione. To further investigate the role of this steroid-metabolizing enzyme in intact cells, we produced stable transfectants expressing 17beta-HSD10 or its catalytically inactive Y168F mutant in human embryonic kidney (HEK) 293 cells. It was found that DHT levels in HEK 293 cells expressing 17beta-HSD10, but not its catalytically inactive mutant, will dramatically increase if adiol is added to culture media. Moreover, certain malignant prostatic epithelial cells have more 17beta-HSD10 than normal controls, and can generate DHT, the most potent androgen, from adiol. This event might promote prostate cancer growth. Analysis of the 17beta-HSD10 sequence shows that this enzyme does not have any ER retention signal or transmembrane segments and has not originated by divergence from a retinol dehydrogenase. The data suggest that the unique mitochondrial location of this HSD [Eur. J. Biochem. 268 (2001) 4899] does not prevent it from oxidizing the 3alpha-hydroxyl group of a C19 sterol in living cells. The experimental results lead to the conclusion that mitochondrial 17beta-HSD10 plays a significant part in a non-classical androgen synthesis pathway along with microsomal retinol dehydrogenases.
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PMID:Oxidative 3alpha-hydroxysteroid dehydrogenase activity of human type 10 17beta-hydroxysteroid dehydrogenase. 1467 39

The growth and development of the prostate gland are regulated by androgens. Despite our understanding of molecular actions of 5alpha-dihydrotestosterone (5alpha-DHT) in the prostate through the trans-activation of the androgen receptor (AR), comprehensive analysis of androgen responsive genes (ARGs) has just been started. Moreover, expression changes induced by the androgen effects of 5alpha-androstane-3alpha,17beta-diol (3alpha-diol), a metabolite of 5alpha-DHT through the action of 3alpha-hydroxysteroid dehydrogenases (3alpha-HSDs), remain undefined. We demonstrated that both 5alpha-DHT and 3alpha-diol stimulated similar levels of androgen sensitive human prostate cancer LNCaP cell proliferation. However, consistent with the fact that 3alpha-diol has low affinity toward the AR, 3alpha-diol did not elicit the same levels of AR trans-activation activity as that of 5alpha-DHT. Since LNCaP cells respond to androgen stimulation by transcriptionally activating the AR downstream genes, gene expression patterns between 0 and 48 h following 3alpha-diol and 5alpha-DHT stimulation were analyzed using cDNA-based membrane arrays to define the temporal regulation of ARGs. Array analysis identified 217 and 219 androgen-modulated genes in at least one time point following 3alpha-diol and 5alpha-DHTstimulation, respectively, including key regulators of cell proliferation. Only a subset of these genes (143) was regulated by both androgens. These data suggest that 3alpha-diol exerts androgenic effects independent of the action of 5alpha-DHT in steroid target tissues. Accordingly, 3alpha-diol might activate cell proliferation cascades independent of AR pathway in the prostate.
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PMID:Partitioning of 5alpha-dihydrotestosterone and 5alpha-androstane-3alpha, 17beta-diol activated pathways for stimulating human prostate cancer LNCaP cell proliferation. 1527 23

Prostate cancer growth depends, in its earlier stages, on androgens and is usually pharmacologically modulated with androgen blockade. However, androgen-ablation therapy may generate androgen-independent prostate cancer, often characterized by an increased invasiveness. We have found that the 5alpha-reduced testosterone derivative, dihydrotestosterone (the most potent natural androgen) inhibits cell migration with an androgen receptor-independent mechanism. We have shown that the dihydrotestosterone metabolite 5alpha-androstane-3beta,17beta-diol (3beta-Adiol), a steroid which does not bind androgen receptors, but efficiently binds the estrogen receptor beta (ERbeta), exerts a potent inhibition of prostate cancer cell migration through the activation of the ERbeta signaling. Very surprisingly, estradiol is not active, suggesting the existence of different pathways for ERbeta activation in prostate cancer cells. Moreover, 3beta-Adiol, through ERbeta, induces the expression of E-cadherin, a protein known to be capable of blocking metastasis formation in breast and prostate cancer cells. The inhibitory effects of 3beta-Adiol on prostate cancer cell migration is counteracted by short interfering RNA against E-cadherin. Altogether, the data showed that (a) circulating testosterone may act with estrogenic effects downstream in the catabolic process present in the prostate, and (b) that the estrogenic effect of testosterone derivatives (ERbeta-dependent) results in the inhibition of cell migration, although it is apparently different from that linked to estradiol on the same receptor and may be protective against prostate cancer invasion and metastasis. These results also shed some light on clinical observations suggesting that alterations in genes coding for 3beta-hydroxysteroid dehydrogenases (the enzymes responsible for 3beta-Adiol formation) are strongly correlated with hereditary prostate cancer.
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PMID:The androgen derivative 5alpha-androstane-3beta,17beta-diol inhibits prostate cancer cell migration through activation of the estrogen receptor beta subtype. 1595 94

Type 2 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD) is a multi-functional enzyme that possesses 3alpha-, 17beta- and 20alpha-HSD, as well as prostaglandin (PG) F synthase activities and catalyzes androgen, estrogen, progestin and PG metabolism. Type 2 3alpha-HSD was cloned from human prostate, is a member of the aldo-keto reductase (AKR) superfamily and was named AKR1C3. In androgen target tissues such as the prostate, AKR1C3 catalyzes the conversion of Delta(4)-androstene-3,17-dione to testosterone, 5alpha-dihydrotestosterone to 5alpha-androstane-3alpha,17beta-diol (3alpha-diol), and 3alpha-diol to androsterone. Thus AKR1C3 may regulate the balance of androgens and hence trans-activation of the androgen receptor in these tissues. Tissue distribution studies indicate that AKR1C3 transcripts are highly expressed in human prostate. To measure AKR1C3 protein expression and its distribution in the prostate, we raised a monoclonal antibody specifically recognizing AKR1C3. This antibody allowed us to distinguish AKR1C3 from other AKR1C family members in human tissues. Immunoblot analysis showed that this monoclonal antibody binds to one species of protein in primary cultures of prostate epithelial cells and in LNCaP prostate cancer cells. Immunohistochemistry with this antibody on human prostate detected strong nuclear immunoreactivity in normal stromal and smooth muscle cells, perineurial cells, urothelial (transitional) cells, and endothelial cells. Normal prostate epithelial cells were only faintly immunoreactive or negative. Positive immunoreactivity was demonstrated in primary prostatic adenocarcinoma in 9 of 11 cases. Variable increases in immunoreactivity for AKR1C3 was also demonstrated in non-neoplastic changes in the prostate including chronic inflammation, atrophy and urothelial (transitional) cell metaplasia. We conclude that elevated expression of AKR1C3 is highly associated with prostate carcinoma. Although the biological significance of elevated AKR1C3 in prostatic carcinoma is uncertain, AKR1C3 may be responsible for the trophic effects of androgens and/or PGs on prostatic epithelial cells.
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PMID:Increased expression of type 2 3alpha-hydroxysteroid dehydrogenase/type 5 17beta-hydroxysteroid dehydrogenase (AKR1C3) and its relationship with androgen receptor in prostate carcinoma. 1660 Dec 86

The present study reports effects of androgens and estrogens on human CYP7B1 transcription in prostate cancer LNCaP cells. Studies with rodents have suggested a role for the CYP7B1 enzyme in balancing cellular hormone levels important for prostate growth. Little is, however, known about the regulation of human CYP7B1. The current study showed strong suppression of a human CYP7B1 luciferase reporter gene by dihydrotestosterone (DHT) in prostate cancer LNCaP cells. Also, DHT and overexpression of androgen receptor (AR) suppressed CYP7B1 promoter activity and CYP7B1-mediated catalysis in kidney-derived HEK293 cells. Effects on CYP7B1 transcription were observed also by estrogen receptors (ER). The effects appeared different for different estrogens. CYP7B1 was stimulated by synthetic ER agonists but suppressed by 17beta-estradiol and 5alpha-androstane-3beta,17beta-diol in LNCaP cells. Our data indicate an important role for CYP7B1 in balancing prostate hormone levels in human cells. In particular, the data suggest that androgens may control intraprostatic levels of estrogen via regulation of CYP7B1-mediated metabolism.
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PMID:Regulation of steroid hydroxylase CYP7B1 by androgens and estrogens in prostate cancer LNCaP cells. 1663 May 58

Androgens as well as monohydroxy-fatty acids are implicated in the pathogenesis of prostate cancer. Like a huge variety of endo- and xenobiotics, they are eliminated as glucuronide conjugates formed by uridine diphosphate-glucuronosyltransferase (UGT) enzymes. In the present study, we observe that treatment of the prostate cancer cells LNCaP with natural and synthetic androgens, IL-1alpha, or epidermal growth factor (EGF) differently modulates the glucuronidation of androgen and bioactive lipid metabolites. Indeed, glucuronidation of 5alpha-androstane-3alpha,17beta-diol and 13-hydroxyoctadecadienoic acid was drastically reduced, whereas 12-hydroxyeicosatetraenoic acid conjugation by UGT was increased after androgen treatment. These effects reflected the reduction of UGT2B10, -B15, and -B17 enzyme expression, and the activation of the UGT2B11 gene. In human prostate epithelial cells, only UGT2B11 and -B15 mRNAs are detected and are regulated by androgens in a similar manner as in LNCaP cells. In LNCaP cells, IL-1alpha and EGF also regulate UGT2B expression in an isoform-specific manner; IL-1alpha induced UGT2B10 and reduced UGT2B17, while having no effects on UGT2B11 mRNA levels. EGF treatment resulted in a decreased UGT2B17 expression, whereas UGT2B10 and -B11 mRNA remained at their basal levels. Overall, these results demonstrate that in the human prostate, androgens do not only affect their own inactivation but also influence the levels of monohydroxy-fatty acids by regulating the expression of UGT2B enzymes in an isoform-specific manner. These differential effects of androgens, IL-1alpha, and EGF on lipid metabolism likely constitute an additional mechanism by which these endogenous factors promote prostate cancer development.
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PMID:Isoform-specific regulation of uridine diphosphate-glucuronosyltransferase 2B enzymes in the human prostate: differential consequences for androgen and bioactive lipid inactivation. 1688 6

We previously reported the selective loss of AKR1C2 and AKR1C1 in prostate cancers compared with their expression in paired benign tissues. We now report that dihydrotestosterone (DHT) levels are significantly greater in prostate cancer tumors compared with their paired benign tissues. Decreased catabolism seems to account for the increased DHT levels as expression of AKR1C2 and SRD5A2 was reduced in these tumors compared with their paired benign tissues. After 4 h of incubation with benign tissue samples, (3)H-DHT was predominantly catabolized to the 5alpha-androstane-3alpha,17beta-diol metabolite. Reduced capacity to metabolize DHT was observed in tumor samples from four of five freshly isolated pairs of tissue samples, which paralleled loss of AKR1C2 and AKR1C1 expression. LAPC-4 cells transiently transfected with AKR1C1 and AKR1C2, but not AKR1C3, were able to significantly inhibit a dose-dependent, DHT-stimulated proliferation, which was associated with a significant reduction in the concentration of DHT remaining in the media. R1881-stimulated proliferation was equivalent in all transfected cells, showing that metabolism of DHT was responsible for the inhibition of proliferation. PC-3 cells overexpressing AKR1C2 and, to a lesser extent, AKR1C1 were able to significantly inhibit DHT-dependent androgen receptor reporter activity, which was abrogated by increasing DHT levels. We speculate that selective loss of AKR1C2 in prostate cancer promotes clonal expansion of tumor cells by enhancement of androgen-dependent cellular proliferation by reducing DHT metabolism.
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PMID:Impaired dihydrotestosterone catabolism in human prostate cancer: critical role of AKR1C2 as a pre-receptor regulator of androgen receptor signaling. 1728 74

In our efforts to develop compounds with therapeutic potential as antiandrogens, we synthesized a series of 5alpha-androstane-3alpha,17beta-diol derivatives with a fixed side-chain length of 3-methylenes at C-16alpha, but bearing a diversity of functional groups at the end. Among these, the chloride induced the best antiproliferative activity on androgen-sensitive Shionogi cells. Substituting the OH at C-3 by a methoxy group showed the importance of the OH. Moreover, its transformation into a ketone increased the androgen receptor (AR) binding but decreased the antiproliferative activity and induced a proliferative effect on Shionogi cells. These results confirm the importance of keeping a 5alpha-androstane-3alpha,17beta-diol nucleus instead of a dihydrotestosterone nucleus. Variable side-chain lengths of 2-, 3-, 4-, and 6-methylenes at C-16alpha were investigated and the optimal length was found to be 3-methylenes. Although exhibiting a weak AR binding affinity, 16alpha-(3'-chloropropyl)-5alpha-androstane-3alpha,17beta-diol (15) provided an antiproliferative activity on Shionogi cells similar to that of pure non-steroidal antiandrogen hydroxy-flutamide (77% and 67%, respectively, at 0.1 microM). The new steroidal compound, 15, thus constitutes a good starting point for development of future antiandrogens with a therapeutic potential against prostate cancer.
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PMID:Chemical synthesis and biological activities of 16alpha-derivatives of 5alpha-androstane-3alpha,17beta-diol as antiandrogens. 1733 33

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