Monoclonal antibodies that inhibit the enzyme activity of NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase.
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ABSTRACT:
SUBMITTER: Tai CL
PROVIDER: S-EPMC1131246 | biostudies-other | 1990 Apr
REPOSITORIES: biostudies-other
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Project description:Multiple lines of evidence have suggested a role for both bile acids and prostaglandins (PG) in gastrointestinal carcinogenesis. Levels of PGE(2) are determined by both synthesis and catabolism. Previously, bile acid-mediated induction of cyclooxygenase-2 (COX-2) was found to stimulate PGE(2) synthesis. NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the key enzyme responsible for the catabolism of PGE(2), has been linked to colorectal carcinogenesis. In this study, we determined whether bile acids altered the expression of 15-PGDH in human colon cancer cell lines. Treatment with unconjugated bile acids (chenodeoxycholate and deoxycholate) suppressed the transcription of 15-PGDH, resulting in reduced amounts of 15-PGDH mRNA, protein, and enzyme activity. Conjugated bile acids were less potent suppressors of 15-PGDH expression than unconjugated bile acids. Treatment with chenodeoxycholate activated protein kinase C (PKC), leading in turn to increased extracellular signal-regulated kinase (ERK) 1/2 activity. Small molecules that inhibited bile acid-mediated activation of PKC and ERK1/2 also blocked the downregulation of 15-PGDH. Bile acids induced early growth response factor-1 (Egr-1) and Snail, a repressive transcription factor that bound to the 15-PGDH promoter. Silencing Egr-1 or Snail blocked chenodeoxycholate-mediated downregulation of 15-PGDH. Together, these data indicate that bile acids activate the signal transduction pathway PKC --> ERK1/2 --> Egr-1 --> Snail and thereby suppress 15-PGDH transcription. Bile acids appear to increase the release of PGs from cells by downregulating catabolism in addition to stimulating synthesis. These results provide new mechanistic insights into the link between bile acids and gastrointestinal carcinogenesis.
| S-EPMC2739822 | biostudies-other
Project description:The structure-activity relationship (SAR) study of two chemotypes identified as inhibitors of the human NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase (HPGD, 15-PGDH) was conducted. Top compounds from both series displayed potent inhibition (IC50 <50 nM), demonstrate excellent selectivity towards HPGD and potently induce PGE2 production in A549 lung cancer and LNCaP prostate cancer cells.
| S-EPMC3970110 | biostudies-literature
Project description:15-Hydroxyprostaglandin dehydrogenase (15-PGDH, EC 1.1.1.141) is the key enzyme for the inactivation of prostaglandins, regulating processes such as inflammation or proliferation. The anabolic pathways of prostaglandins, especially with respect to regulation of the cyclooxygenase (COX) enzymes have been studied in detail; however, little is known about downstream events including functional interaction of prostaglandin-processing and -metabolizing enzymes. High-affinity probes for 15-PGDH will, therefore, represent important tools for further studies.To identify novel high-affinity inhibitors of 15-PGDH we performed a quantitative high-throughput screen (qHTS) by testing >160 thousand compounds in a concentration-response format and identified compounds that act as noncompetitive inhibitors as well as a competitive inhibitor, with nanomolar affinity. Both types of inhibitors caused strong thermal stabilization of the enzyme, with cofactor dependencies correlating with their mechanism of action. We solved the structure of human 15-PGDH and explored the binding modes of the inhibitors to the enzyme in silico. We found binding modes that are consistent with the observed mechanisms of action.Low cross-reactivity in screens of over 320 targets, including three other human dehydrogenases/reductases, suggest selectivity of the present inhibitors for 15-PGDH. The high potencies and different mechanisms of action of these chemotypes make them a useful set of complementary chemical probes for functional studies of prostaglandin-signaling pathways.This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S2.
| S-EPMC2970562 | biostudies-literature
Project description:The NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH) catalyzes the oxidation of the 15(S)-hydroxyl group of prostaglandin E2 (PGE2), converting the pro-inflammatory PGE2 to the anti-inflammatory 15-keto-PGE2 (an endogenous ligand for peroxisome proliferator-activated receptor-gamma [PPAR-γ]). To evaluate the significance of 15-PGDH/15-keto-PGE2 cascade in liver inflammation and tissue injury, we generated transgenic mice with targeted expression of 15-PGDH in the liver (15-PGDH Tg) and the animals were subjected to lipopolysaccharide (LPS)/Galactosamine (GalN)-induced acute liver inflammation and injury. Compared to the wild type mice, the 15-PGDH Tg mice showed lower levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), less liver tissue damage, less hepatic apoptosis/necrosis, less macrophage activation, and lower inflammatory cytokine production. In cultured Kupffer cells, treatment with 15-keto-PGE2 or the conditioned medium (CM) from 15-PGDH Tg hepatocyes inhibited LPS-induced cytokine production, in vitro. Both 15-keto-PGE2 and the CM from15-PGDH Tg hepatocyes also up-regulated the expression of PPAR-γ downstream genes in Kupffer cells. In cultured hepatocytes, 15-keto-PGE2 treatment or 15-PGDH overexpression did not influence TNF-α-induced hepatocyte apoptosis. These findings suggest that 15-PGDH protects against LPS/GalN-induced liver injury and the effect is mediated via 15-keto-PGE2, which activates PPAR-γ in Kupffer cells and thus inhibits their ability to produce inflammatory cytokines. Accordingly, we observed that the PPAR-γ antagonist, GW9662, reversed the effect of 15-keto-PGE2 in Kupffer cell in vitro and restored the susceptibility of 15-PGDH Tg mice to LPS/GalN-induced acute liver injury in vivo. Collectively, our findings suggest that 15-PGDH-derived 15-keto-PGE2 from hepatocytes is able to activate PPAR-γ and inhibit inflammatory cytokine production in Kupffer cells and that this paracrine mechanism negatively regulates LPS-induced necro-inflammatory response in the liver. Therefore, induction of 15-PGDH expression or utilization of 15-keto-PGE2 analogue may have therapeutic benefits for the treatment of endotoxin-associated liver inflammation/injury.
| S-EPMC5397067 | biostudies-literature
Project description:Background15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is a metabolic antagonist of COX-2, catalyzing the degradation of inflammation mediator prostaglandin E2 (PGE2) and other prostanoids. Recent studies have established the 15-PGDH gene as a colon cancer suppressor.MethodsWe evaluated 15-PDGH as a colon cancer susceptibility locus in a three-stage design. We first genotyped 102 single-nucleotide polymorphisms (SNPs) in the 15-PGDH gene, spanning ?50 kb up and down-stream of the coding region, in 464 colon cancer cases and 393 population controls. We then genotyped the same SNPs, and also assayed the expression levels of 15-PGDH in colon tissues from 69 independent patients for whom colon tissue and paired germline DNA samples were available. In the final stage 3, we genotyped the 9 most promising SNPs from stages 1 and 2 in an independent sample of 525 cases and 816 controls (stage 3).ResultsIn the first two stages, three SNPs (rs1365611, rs6844282 and rs2332897) were statistically significant (p<0.05) in combined analysis of association with risk of colon cancer and of association with 15-PGDH expression, after adjustment for multiple testing. For one additional SNP, rs2555639, the T allele showed increased cancer risk and decreased 15-PGDH expression, but just missed statistical significance (p-adjusted?=?0.063). In stage 3, rs2555639 alone showed evidence of association with an odds ratio (TT compared to CC) of 1.50 (95% CI?=?1.05-2.15, p?=?0.026).ConclusionsOur data suggest that the rs2555639 T allele is associated with increased risk of colon cancer, and that carriers of this risk allele exhibit decreased expression of 15-PGDH in the colon.
| S-EPMC3661460 | biostudies-literature
Project description:Human promyelocytic leukaemia (HL-60) cells were employed to study the induction of NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the key enzyme in controlling prostaglandin inactivation. Phorbol 12-myristate 13-acetate (PMA) stimulated 15-PGDH activity in a time- and concentration-dependent manner. Dimethyl sulphoxide (DMSO) also stimulated the enzyme activity, although a much delayed stimulation was observed. Western blot studies indicated that PMA increased significantly a 28 kDa immunoreactive protein characteristic of 15-PGDH. L-[35S]Methionine labelling of the PMA-treated cells showed a similar enhancement over the control cells. These studies indicate that PMA induced synthesis of 15-PGDH. Stimulation of 15-PGDH activity by PMA or DMSO appears to be mediated by protein kinase C activation, since an inactive analogue of PMA failed to induce the effect, and both staurosporine and H-7 blocked the stimulation. Stimulation by PMA was optimal at 10 nM and less effective at higher concentrations. Western blot studies indicated that a similar, if not greater, amount of enzyme protein was induced at high concentrations of PMA, suggesting that enzyme inactivation might be occurring. Possible enzyme inactivation by protein kinase C activation was further examined by incubating DMSO-treated cells with a high concentration of PMA (50 nM). Time-dependent inactivation of 15-PGDH within the first 1 h was observed and this inactivation was partially blocked by staurosporine and H-7. Pulse-chase experiments indicated that 15-PGDH had a rapid turnover rate (t 1/2 = 47 min), and PMA shortened the half-life of the enzyme (t 1/2 = 33 min), suggesting that PMA might have an additional effect on 15-PGDH degradation. The rapid turnover of 15-PGDH indicates that the enzyme activity depends on continued enzyme synthesis, and this could be susceptible to hormone and drug control mechanisms.
| S-EPMC1151639 | biostudies-other
Project description:MicroRNA contribute to tumor radiation resistance, which is an important clinical problem, and thus we are interested in identifying and characterizing their function. We demonstrate that miR-620 contributes to radiation resistance in cancer cells by increasing proliferation, and decreasing the G2/M block. We identify the hydroxyprostaglandin dehydrogenase 15-(nicotinamide adenine dinucleotide) (HPGD/15-PGDH) tumor suppressor gene as a direct miR-620 target, which results in increased prostaglandin E2 (PGE2) levels. Furthermore, we show that siRNA targeting of HPGD or administration of exogenous PGE2 recapitulates radioresistance. Targeting of the EP2 receptor that responds to PGE2 using pharmacological or genetic approaches, abrogates radioresistance. Tumor xenograft experiments confirm that miR-620 increases proliferation and tumor radioresistance in vivo. Regulation of PGE2 levels via targeting of HPGD by miR-620 is an innovative manner by which a microRNA can induce radiation resistance.
| S-EPMC4673174 | biostudies-literature
Project description:15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is a prostaglandin-degrading enzyme that is highly expressed in normal colon mucosa but is ubiquitously lost in human colon cancers. Herein, we demonstrate that 15-PGDH is active in vivo as a highly potent suppressor of colon neoplasia development and acts in the colon as a required physiologic antagonist of the prostaglandin-synthesizing activity of the cyclooxygenase 2 (COX-2) oncogene. We first show that 15-PGDH gene knockout induces a marked 7.6-fold increase in colon tumors arising in the Min (multiple intestinal neoplasia) mouse model. Furthermore, 15-PGDH gene knockout abrogates the normal resistance of C57BL/6J mice to colon tumor induction by the carcinogen azoxymethane (AOM), conferring susceptibility to AOM-induced adenomas and carcinomas in situ. Susceptibility to AOM-induced tumorigenesis is mediated by a marked induction of dysplasia, proliferation, and cyclin D1 expression throughout microscopic aberrant crypt foci arising in 15-PGDH null colons and is concomitant with a doubling of prostaglandin E(2) in 15-PGDH null colonic mucosa. A parallel role for 15-PGDH loss in promoting the earliest steps of colon neoplasia in humans is supported by our finding of a universal loss of 15-PGDH expression in microscopic colon adenomas recovered from patients with familial adenomatous polyposis, including adenomas as small as a single crypt. These models thus delineate the in vivo significance of 15-PGDH-mediated negative regulation of the COX-2 pathway and moreover reveal the particular importance of 15-PGDH in opposing the neoplastic progression of colonic aberrant crypt foci.
| S-EPMC1567703 | biostudies-literature
Project description:Elevated prostaglandin E2 (PGE2) levels are observed in colorectal cancer (CRC) patients, and this increase is associated with poor prognosis. Increased synthesis of PGE2 in CRC has been shown to occur through COX-2-dependent mechanisms; however, loss of the PGE2-catabolizing enzyme, 15-hydroxyprostaglandin dehydrogenase (15-PGDH, HPGD), in colonic tumors contributes to increased prostaglandin levels and poor patient survival. While loss of 15-PGDH can occur through transcriptional mechanisms, we demonstrate that 15-PGDH can be additionally regulated by a miRNA-mediated mechanism. We show that 15-PGDH and miR-21 are inversely correlated in CRC patients, with increased miR-21 levels associating with low 15-PGDH expression. 15-PGDH can be directly regulated by miR-21 through distinct sites in its 3' untranslated region (3'UTR), and miR-21 expression in CRC cells attenuates 15-PGDH and promotes increased PGE2 levels. Additionally, epithelial growth factor (EGF) signaling suppresses 15-PGDH expression while simultaneously enhancing miR-21 levels. miR-21 inhibition represses CRC cell proliferation, which is enhanced with EGF receptor (EGFR) inhibition. These findings present a novel regulatory mechanism of 15-PGDH by miR-21, and how dysregulated expression of miR-21 may contribute to loss of 15-PGDH expression and promote CRC progression via increased accumulation of PGE2.
| S-EPMC6443653 | biostudies-literature
Project description:Bioactive lipids govern cellular homeostasis and pathogenic inflammatory processes. Current dogma holds that bioactive lipids, such as prostaglandins and lipoxins, are inactivated by 15-hydroxyprostaglandin dehydrogenase (15PGDH). In contrast, the present results reveal that catabolic "inactivation" of hydroxylated polyunsaturated fatty acids (PUFAs) yields electrophilic ?,?-unsaturated ketone derivatives. These endogenously produced species are chemically reactive signaling mediators that induce tissue protective events. Electrophilic fatty acids diversify the proteome through post-translational alkylation of nucleophilic cysteines in key transcriptional regulatory proteins and enzymes that govern cellular metabolic and inflammatory homeostasis. 15PGDH regulates these processes as it is responsible for the formation of numerous electrophilic fatty acids including the arachidonic acid metabolite, 15-oxoeicosatetraenoic acid (15-oxoETE). Herein, the role of 15-oxoETE in regulating signaling responses is reported. In cell cultures, 15-oxoETE activates Nrf2-regulated antioxidant responses (AR) and inhibits NF-?B-mediated pro-inflammatory responses via IKK? inhibition. Inhibition of glutathione S-transferases using ethacrynic acid incrementally increased the signaling capacity of 15-oxoETE by decreasing 15-oxoETE-GSH adduct formation. This work demonstrates that 15PGDH plays a role in the regulation of cell and tissue homeostasis via the production of electrophilic fatty acid signaling mediators.
| S-EPMC4414684 | biostudies-literature