hydroxyprostaglandin dehydrogenases

....

..The association between the expression of androgen receptor (AR) or androgen-converting enzymes and malignant potential in prostate cancer (PCa) was examined...

..Our results suggested that both AKR1C2 and AKR1C3 mediate similar PGD2 conversion toward the accumulation of proliferative signals through FP and PI3K/Akt signaling pathways to promote prostate cell proliferation...

..Among these compounds, ciglitazone appeared to be the most powerful inhibitor (IC(50)=2.7 microM). Inhibition by ciglitazone was non-competitive with respect to NAD(+) and uncompetitive with respect to PGE(2)...

..This regulatory site appears to overlap with the activator site occupied by imipramine since activation of the enzyme by this activator is competitively inhibited by compound CT-8...

..The multi-specificity contributes significantly to steroid metabolism in peripheral tissues, due to the high levels of 17beta-HSD5 mRNA in both breast and prostate tissues...

..These features warrant future studies of AKR1C3 in both hormone- and non-hormone-associated tissues and identification of the rodent homolog for establishing animal models...

..Here, these three pathways of PGF synthesis by these enzymes are reviewed, and the physiological roles of the enzymes are discussed...

....

..The C-terminal region appears to be more important for the interaction of the enzyme with the prostaglandin substrates than with the coenzyme...

..These results suggest that Ile-17, Asn-91, and Val-186 are involved in the interaction with NAD(+) and contribute to the full catalytic activity of 15-PGDH...

..CK20, AN43 and PGDH decreased but COX-2 expression increased in higher stage tumors. The histologic phenotype of these cancers is reflected in their expression of these proteins and is modified further as tumors progress in stage...

..However, reduced AKR1C3 expression cannot distinguish hyperplastic endometrium from endometrial adenocarcinoma of endometrial type. The biologic and pathological roles of AKR1C3 in endometrial epithelium require further investigation...

..The aim of this study was to determine if the differences in enzyme activities between tumorous and nontumorous breast tissues are associated with differences in progesterone metabolizing enzyme gene expression...

..The protein has four cysteine residues (five with the positional microheterogeneity), but there is no evidence for functional importance of any of these residues.(ABSTRACT TRUNCATED AT 250 WORDS)..

..4 kilobases and the other of 2.0 kilobases. Isolation of the cDNA for 15-hydroxyprostaglandin dehydrogenase should facilitate studies on the structure, function, and regulation of this enzyme...

..In summary, these results suggest a novel tumor suppressive role for 15-PGDH due to loss of expression during colorectal tumor progression...

..These findings thus delineate an enzymatic pathway that induces colon cancer suppression, a pathway that is activated by TGF-beta and mediated by 15-PGDH...

..These results suggest that tumor suppressive action of these agents may, in part, be related to their ability to induce 15-PGDH expression...

..The data underline AKR1C3 as a COX-independent target for NSAID and will provide a structural basis for the future development of new cancer therapies with reduced COX-dependent side effects...

..The reagent thus has utility to access the localized expression of AKR1C3 in hormonal dependent malignancies of the breast and prostate...

..These results indicate that enhanced intracellular conversion of adrenal androgens to testosterone and dihydrotestosterone is a mechanism by which prostate cancer cells adapt to androgen deprivation and suggest new therapeutic targets...

..The decrease in amounts of 15-PGDH in inflamed mucosa can be explained at least, in part, by TNF-alpha-mediated suppression of 15-PGDH transcription...

..Future investigation may shed more light on the roles of these enzymes in health and diseases...

....

..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...

..Our results indicate for the first time that 15-PGDH may be a novel tumor suppressor gene in breast cancer, and suggest that this enzyme can modulate the ER pathway...

....

..This effect is reversible in a subset of NSCLC upon treatment with an EGFR TKI...

....

..Furthermore, the expression of 15-PGDH was found to be stimulated by hyaluronidase. These results suggest that 15-PGDH may decrease the level of proliferative PGE2, induce apoptosis and function like a tumor suppressor...

..These data indicate that PGDH may serve a tumor suppressor function in colorectal cancer and provide a possible COX-2-independent way to target PGE(2) to inhibit cancer progression...

....

..Thus, whereas compromise of the Ptges/PGE2/Ptger2 pathway does not alter airway responsiveness, genetic modulation that elevates PGE2 levels in the lung attenuates airway responsiveness...

..Here, we report that ciglitazone downregulates PGE2 in NSCLC cells...

..We aimed to test associations between body fat or fat distribution and mRNA transcript levels for androgen and oestrogen receptors and for enzymes metabolizing sex steroids in adipose tissue...

..Moreover, high expression of both PG synthases after initiation of implantation may indicate their significant role in placentation...

..The expression of COX2, PTGFS, and mPTGES1 mRNA and/or protein was confined in the cervical glandular epithelial cells of nonpregnant sheep...

..All these observations support the concept that prostaglandins might be involved in hair growth and differentiation control...

....

..Increased progesterone and/or dihydrotestosterone reduction in abdominal adipose tissue may impact locally on fat cell metabolism...

..Thus, spermatozoa may bear a role in accelerating their own transport into the fertilization site...

..Overall, our studies demonstrate that IL-4 has the capacity to inhibit COX-2 mRNA transcription in NSCLC cells and the inhibition of PGE(2) appears to be predominately COX-2 dependent...

..Docking of the flavones in the active site of AKR1C1 revealed their possible binding modes, in which they are sandwiched between the Leu308 and Trp227 of AKR1C1...

....

....

..Thus, endocrine control of labor has the capacity to plastically adapt to changes in genetically determined prostaglandin signals...

..Our data suggests that exogenous NO inhibits 9-KPR activity in HFM, thus modulating the synthesis of important labor mediators as PGF(2alpha)...

..These compounds can now be used to determine the role of AKR1C3 in producing two proliferative signals in the prostate namely testosterone and 9alpha,11beta-PGF2...

..Moreover, high expression of conceptus PGHS-1, mPGES-1, PGFS, and CBR1 after initiation of implantation suggests their significant role in placentation...

..In addition, the positive correlation between PGHS1 and BMI offers the novel hypothesis that the regulation of PG synthesis may have a role in determining fat distribution in human obesity...

..The low hepatic formation of 3alpha-hydroxytibolone suggests that AKR1C4 is not the primary source of this metabolite and instead it maybe formed by an intestinal or enterobacterial 3alpha-HSD...

..It is suggested that the expression of AKR1C1 and AKR1C3 in endometrial cancer will govern the ratio of P:E2...

..We conclude that, along with COX-2, dynamic compression induces mPGES-1 mRNA and protein expression in cartilage explants. Thus, the mechanosensitive mPGES-1 enzyme represents a potential therapeutic target in osteoarthritis...

..The authors conclude that upon stimulation with the same upstream signals, different downstream intracellular pathways regulate PTGS2 and PGDH mRNA expression...

....

..By contrast the PGF(2alpha) system is activated during luteal regression. Collectively, our results suggest an integrated role for luteal PGE(2) and PGF(2alpha) in autoregulation of CL function...

..Our findings suggest a differential role for uterine stroma and epithelium in vivo whereby the former acts to remove (via PGDH), and the latter to produce (via COX-2) biologically active prostaglandin...

....

..This case suggests that rapid cycling is a systemic disease, resembling hibernation, with prostaglandins playing a mediator role...

....

....

....

..11beta-HSD2 up-regulation may also lead to an increase in PGDH mRNA concentrations that, until term, possibly delays myometrial contractions induced by prostaglandins...

..We conclude that cortisol inhibits PGDH activity and expression and that progestagens increase PGDH activity in human chorion and placenta...

..Furthermore, these results suggest that the rat is not an adequate model for investigating the biological activities of 2-arachidonylglycerol or glyceryl prostaglandins in humans...

..High homology between human 20alpha-HSD [AKR 1C1] cDNA with other AKRs had caused difficulty in gene isolation and expression analysis. Thus, the metabolism of progesterone in the human reproductive system remained unclear...

..Taken together, our results suggest the presence of a novel, membrane-associated form of PGFS that is stimulus-inducible and is likely to be preferentially coupled with COX-2...

..The TLR-4 may mediate bacterially induced preterm labor via regulation of prostaglandin degradation rather than prostaglandin synthesis...

....

..Therefore, the establishment of pregnancy may depend not only on inhibition of endometrial PGF(2alpha), but also on increased PGE(2) production in cattle...

..In addition, OT increased PGD(2) 11-ketoreductase protein expression in myometrium harvested during the porcine estrous cycle. However, the OT-stimulated PGF(2)alpha myometrial secretion was observed in both, cycling and pregnant gilts...

..Since PGE(2) is a cytoprotective eicosanoid, the failure to produce this metabolite in cells isolated from the IC bladder may represent an increased susceptibility to damage by proinfammatory stimuli...

..This observation indicates that both preterm and term cervical ripening is associated with decreased degradation of prostaglandins...

..Mice deficient in 5alpha-reductase type I fail to undergo cervical ripening at term despite the timely onset of luteolysis and progesterone withdrawal in blood...

..The findings point to PGFS expression as a key factor in regulating the uterotonic process in the sheep...

..Since the substrate binding cavity of PGFS is relatively large in comparison with those of AKR1C1 and AKR1C2, PGFS (AKR1C3) could catalyze the reduction and/or oxidation reactions of various compounds over a relatively wide pH range...

..These data demonstrate that PGE(2) is a critical mediator of immunosuppression in thermally injured female mice and that the increase in circulating PGE(2) is derived, in part, from decreased degradation and clearance of PGE(2)...

..M., Abrams, W. R., and Pawlowski, J. E. (1991) J. Biol. Chem. 266, 8826-8834]. The sequence data presented suggests that 3 alpha-HSD, prostaglandin F synthase, and aldehyde/aldose reductases are members of a common gene family...

..These results suggest that PGF2 alpha production may increase at term and change during the estrous cycle and is associated with an increase in uterine PGF synthase concentrations...

....

..Indomethacin, in association with PMA can consequently exert a dual control on key enzymes of PGE2 metabolism without modifying adhesion of the cells...

..Moreover, they suggest that these eicosanoid oxidoreductases have multifaceted roles controlling the levels of specific eicosanoids involved in the regulation of inflammation...

..Others are genes so far unknown to play a role in endometrial-trophoblast interaction and open a wide field of investigation...

..So, in conclusion, putting all these facts together, the inhibitory effect of calcitriol on PGE2 level and its biologic activity may be a novel mechanism for its probable SCC preventive effect...

..In order to expand this mutational spectrum and better delineate the HPGD-related phenotype, we report the clinical and molecular characterisation of a 13-year-old boy and compare his features to known mutated patients...

..An increase in HPGD and SLCO2A1 levels on P22 indicates a tight regulation of PTG action by pregnancy...

..These findings support the role 3 alpha-HSD in inflammation and suggest that hydroxysteroid dehydrogenases, hydroxyprostaglandin dehydrogenases and prostaglandin F2 alpha synthase may be members of a common gene family.

....

..Thus, utilization of omega 3-PUFAs may represent an effective and safe therapeutic approach for the chemoprevention and treatment of human cholangiocarcinoma...

..Here we review published and recent results in the context of the current state of research on breast apocrine cancer...

..The aim of this study was to develop on original compression model for studying the effect of mechanical stress on osteoblasts...

..about ADH catalysis and the stability of dimers, which may also be useful in understanding homologous dehydrogenases, which include the human 17 beta-hydroxysteroid, 11 beta-hydroxysteroid and 15-hydroxyprostaglandin dehydrogenases.

..Only two of these families were of European origin. We wished to determine the role of HPGD in causing PHO in non-consanguineous European families...

..When the alpha-carbon backbone of the cofactor binding domains of the five structures are superimposed, the conserved residues are at the core of the structure and in the cofactor binding domain, but not in the substrate binding pocket...

..These newly discovered molecular mechanisms in the pathogenesis of lung cancer provide novel opportunities for targeted therapy and prevention in lung cancer...

..In summary, these studies show unexpected relationships between thiamine metabolism and genes that may be involved in the oncogenesis of breast and lung cancer...

..Both calcitriol and genistein are relatively safe and have little toxicity associated with their intake. We postulate that the combination of calcitriol and genistein is an attractive therapeutic option for the treatment of PCa...

..Calcitriol or its analogs may have utility as chemopreventive agents and should be evaluated in clinical trials in PCa patients with early or precancerous disease...

....

..It is becoming increasing apparent that the targeting of a single molecule will not be as effective as is needed to have a significant impact on this disease. ..

..This study of genetic variation in the prostaglandin/EGFR pathway will provide insights into the complex process of colorectal carcinogenesis, and increase understanding of the pharmacogenetics of NSAID chemoprevention. ..

..To identify the genes in the PGE2 pathway controlling renin expression and release. 2. To define the capacity of mPGE synthases to modulate kidney function. 3. To define the impact of PGE2 metabolism by 15-PGDH on renal functions. ..

..To identify the genes in the PGE2 pathway controlling renin expression and release. 2. To define the capacity of mPGE synthases to modulate kidney function. 3. To define the impact of PGE2 metabolism by 15-PGDH on renal functions. ..

..The results of this research program should provide a molecular basis of our understanding of the regulatory mechanisms and the structural and function of two key catabolic enzymes of prostaglandins. ..

..Furthermore, the program should uncover novel properties of 5-HEDH and shed some light on the role of this enzyme in the inflammatory and allergic reactions. ..

..Finally, we plan to elucidate the molecular basis of defective prostaglandin metabolism in genetic hypertensive rats. The results of this program should aid in understanding the biochemistry, physiology and pathophysiology of the enzyme...

..This application will establish whether these genetic changes result in abnormal bile-acid production and are causal in these deficiencies. ..

..These studies will inform genotyping and validate genomic studies of cancer of the airway and improve risk assessment prediction. ..

..This may provide insight into the mechanisms leading to infertility (e.g., leuteinized unruptured follice syndrome) and support the developoment of PG synthesis inhibitors of PG synthesis inhibitors for use as contraceptives. ..

....

..The K01 award will culminate in an R01 application that will pave the way for the candidate to become an independent investigator in MCI and AD research. ..

..Validation of a role for AKRs in PAH-induced lung carcinogenesis may target this pathway for prevention and intervention of this disease. ..

..Validation of a role for AKRs in PAH-induced lung carcinogenesis may target this pathway for prevention and intervention of this disease. ..

..abstract_text> ..

..The second portion of the project will examine the effect of modifying anti-oxidant enzymes, again through introduction of sense or anti-sense expression vectors, on the life span of these fibroblasts...

..The mRNA species coding for the human enzyme will be identified by Northern analysis using the cDNA for the rat liver enzyme...

..The mutagenicity of these PAH o-quinones will be assessed using Salmonella tester strains (Ta102 and TA104) which are sensitive to mutagens that cause oxidative DNA damage...

....

..These studies will provide critical information regarding cellular response to oxidative stress and aid in determining if a common regulatory mechanism exists for GSH-dependent enzymes. ..

..Aim 4, will use crystal structures of AKR1C3"NADP(H)"NSAID complexes to develop AKR1C3 isoform specific inhibitors. These studies will establish whether AKR1C3 is a non-Cox target for the cancer chemopreventive roles of NSAIDs. ..

..Completion of these aims will provide structural details of how AKRs transform steroid hormones. ..

..This proposal is aimed at developing a stable isotope dilution liquid chromatography mass spectrometry method to measure the intraprostatic androgen metabolome which could be used to better diagnose and treat prostate cancer. ..

..abstract_text> ..

..These inhibitors may provide tools to dissect function and provide routes to the first Selective Intracrine Modulators that target AKRs. ..