Disease relevance of HPGD

• We find that 15-PGDH transcript and protein are both highly expressed by normal colonic epithelia but are nearly undetectable in colon cancers [1].
• Little is known about the role of the key prostaglandin catabolic enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in breast cancer pathogenesis [2].
• Human lung adenocarcinoma cells, A549, possess the capacity of expressing both cyclooxygenase-2 (COX-2) and NAD(+)-linked 15-hydroxyprostaglandin dehydrogenase (15-PGDH) [3].
• 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 [4].
• 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 [5].

Psychiatry related information on HPGD

• These data suggest that 15-PGDH contributes to the tight regulation of PG action in the endometrium especially at the critical period of recognition of pregnancy [6].

High impact information on HPGD

• Metabolism of PGE2 by prostaglandin dehydrogenase is essential for remodeling the ductus arteriosus [7].
• 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 [4].
• 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 [4].
• 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 [4].
• Using gene transfection to restore 15-PGDH expression in colon cancer cells strongly inhibits the ability of these cells to form tumors in immune-deficient mice and demonstrates 15-PGDH to have functional colon cancer tumor suppressor activity [1].

Chemical compound and disease context of HPGD

• The DNA coding for this alanine mutant 15-PGDH was expressed in E. coli [8].
• Regulation of synthesis and activity of NAD(+)-dependent 15-hydroxy-prostaglandin dehydrogenase (15-PGDH) by dexamethasone and phorbol ester in human erythroleukemia (HEL) cells [9].
• Extracts from E. coli containing these expression plasmids exhibited 15-PGDH activity which was inducible with (IPTG) [10].

Biological context of HPGD

• Transfection assays showed that transient up-regulation of 15-PGDH levels in MDA-MB-231 cells resulted in a decreased clonal growth, and stable up-regulation significantly decreased the ability of these cells to form tumors in athymic mice [2].
• In addition, 15-PGDH levels were down-regulated by estrogen but up-regulated by the tumor suppressor gene CAAT/enhancer binding protein alpha [2].
• In contrast, transient silencing of 15-PGDH in MCF-7 cells resulted in their enhanced proliferation, and a stable silencing in these cells enhanced cell cycle entry in vitro and tumorigenicity in vivo [2].
• Further analysis revealed methylation of the 15-PGDH promoter in one breast cancer cell line and 30% of primary tumors [2].
• We hypothesized that CRH, produced locally in the chorion, could act to modulate PGDH activity throughout gestation [11].

Anatomical context of HPGD

• For example, it is possible that PGDH activity in lower segment chorion may be reduced in those patients with premature cervical softening, or may be particularly high in those patients with an unfavorable cervix, presenting with a low Bishop score and poor progression at the time of labor [12].
• In summary, these studies have suggested that prostaglandin dehydrogenase may have a central role to play in the mechanisms which determine biologically active prostaglandin concentrations within human fetal membranes and placenta at the time of labor, at term or preterm [12].
• If the enzyme in this region crucially determines the passage and availability of biologically active prostaglandins from amnion and chorion to underlying cervix, then pharmacologic manipulation of PGDH activity may effectively regulate PG transfer in these clinical conditions [12].
• In certain regions of the membranes, we suggest that PGDH expression may be influenced by levels of anti-inflammatory and pro-inflammatory cytokines [12].
• Regulation of 15-hydroxy prostaglandin dehydrogenase by corticotrophin-releasing hormone through a calcium-dependent pathway in human chorion trophoblast cells [11].

Associations of HPGD with chemical compounds

• In other regions of the membranes, we suggest that PGDH may be regulated at a transcriptional level by competing activities of progesterone and cortisol [12].
• Cells treated with either BAPTA-AM or EGTA had significantly reduced PGDH activity; and, at intermediate concentrations of chelator, exogenous CRH restored PGDH activity [11].
• The induction of 15-PGDH expression by dexamethasone was blocked by a glucocorticoid receptor antagonist RU 486 and by a nuclear translocation inhibitor geldanamycin, indicating that the induction is a genetic mechanism [13].
• The induction of 15-PGDH expression by dexamethasone and other glucocorticoids at the therapeutic level provides an additional biochemical mechanism for the anti-inflammatory action of these glucocorticoids [13].
• IL-4 did not modulate additional arachidonic acid pathway enzymes mPGES-1 and 15-PGDH, which could potentially be responsible for regulating PGE(2) production [14].

Enzymatic interactions of HPGD

• The primary catabolic pathway of prostaglandins and related eicosanoids is initiated by the oxidation of 15(S)-hydroxyl group catalyzed by NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH) followed by the reduction of delta13 double bond catalyzed by NADPH/NADH dependent delta13-15-ketoprostaglandin reductase (13-PGR) [15].

Regulatory relationships of HPGD

• Treatment with TNF-alpha suppressed the transcription of 15-PGDH in human colonocytes, resulting in reduced amounts of 15-PGDH mRNA and protein and enzyme activity [16].
• Prostaglandins play a key role during in vitro human fetal lung development and are synthesised by prostaglandin H synthase-1 (PGHS-1) and inactivated by 15-hydroxyprostaglandin dehydrogenase (PGDH) with formation of inactive 13,14-dihydro-15-keto-prostaglandins [17].
• 15-PGDH could be induced by IL-6 and forskolin in addition to androgens in a time- and dose-dependent manner but not by other cytokines and growth factors in LNCaP cells [18].
• IL-10 induced the expression of prostaglandin dehydrogenase (PGDH), the major catabolic enzyme involved in prostaglandin degradation [19].

Other interactions of HPGD

• At term, elevated levels of cortisol compete with and displace progesterone from GR, resulting in inhibition of PGDH transcription and activity [12].
• Induction of 15-PGDH expression by TGF-beta1 was synergistically stimulated by the addition of Wnt3A which was inactive by itself [20].
• CK20, AN43 and PGDH decreased but COX-2 expression increased in higher stage tumors [21].
• Here we have examined the enzymes cyclooxygenase (COX)-2 and 15-hydroxyprostaglandin dehydrogenase (15-OH PGDH) in pregnant human cervix [22].
• We suggest that, in chorion trophoblast cells, endogenously produced CRH exerts a tonic stimulatory effect on PGDH activity and may help maintain a metabolic barrier, preventing the transfer of bioactive PGs from the chorioamnion to the myometrium [11].
• We suggest that, in chorion trophoblast cells, CRHR1 and CRHR2 mediate divergent effects on PGDH expression, and this may provide a precise regulation of PGs levels from chorion to myometrium during pregnancy [23].

Analytical, diagnostic and therapeutic context of HPGD

• At cesarean sections (unripe cervix), the level of 15-OH PGDH mRNA was significantly higher than the level in the ripe cervix at the time of partus, irrespective of the gestational length [22].
• This was evident from both the western blot analysis and activity assay of 15-PGDH [3].
• Scriptaid but not nullscript induced a significant accumulation of acetylated histones H3 and H4 which were associated with the 15-PGDH promoter as determined by chromatin immunoprecipitation assay [20].
• Ovarian expression of the NAD+-dependent 15-hydroxy PG dehydrogenase (PGDH) was assessed by RT-PCR, Western blotting, and immunohistochemistry [24].
• By RIA and Northern blotting analysis, all glucocorticoids (GCs) decreased PGDH activity/expression [25].

References