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Gene Review

HPGD  -  hydroxyprostaglandin dehydrogenase 15-(NAD)

Homo sapiens

Synonyms: 15-PGDH, PGDH, PGDH1, PHOAR1, Prostaglandin dehydrogenase 1, ...
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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


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


Biological context of HPGD


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


  1. 15-Hydroxyprostaglandin dehydrogenase, a COX-2 oncogene antagonist, is a TGF-beta-induced suppressor of human gastrointestinal cancers. Yan, M., Rerko, R.M., Platzer, P., Dawson, D., Willis, J., Tong, M., Lawrence, E., Lutterbaugh, J., Lu, S., Willson, J.K., Luo, G., Hensold, J., Tai, H.H., Wilson, K., Markowitz, S.D. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  2. 15-hydroxyprostaglandin dehydrogenase is a tumor suppressor of human breast cancer. Wolf, I., O'Kelly, J., Rubinek, T., Tong, M., Nguyen, A., Lin, B.T., Tai, H.H., Karlan, B.Y., Koeffler, H.P. Cancer Res. (2006) [Pubmed]
  3. Reciprocal regulation of cyclooxygenase-2 and 15-hydroxyprostaglandin dehydrogenase expression in A549 human lung adenocarcinoma cells. Tong, M., Ding, Y., Tai, H.H. Carcinogenesis (2006) [Pubmed]
  4. 15-Hydroxyprostaglandin dehydrogenase is an in vivo suppressor of colon tumorigenesis. Myung, S.J., Rerko, R.M., Yan, M., Platzer, P., Guda, K., Dotson, A., Lawrence, E., Dannenberg, A.J., Lovgren, A.K., Luo, G., Pretlow, T.P., Newman, R.A., Willis, J., Dawson, D., Markowitz, S.D. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  5. Repression of prostaglandin dehydrogenase by epidermal growth factor and snail increases prostaglandin E2 and promotes cancer progression. Mann, J.R., Backlund, M.G., Buchanan, F.G., Daikoku, T., Holla, V.R., Rosenberg, D.W., Dey, S.K., DuBois, R.N. Cancer Res. (2006) [Pubmed]
  6. 15-Hydroxyprostaglandin dehydrogenase in the bovine endometrium during the oestrous cycle and early pregnancy. Parent, M., Madore, E., MacLaren, L.A., Fortier, M.A. Reproduction (2006) [Pubmed]
  7. Metabolism of PGE2 by prostaglandin dehydrogenase is essential for remodeling the ductus arteriosus. Coggins, K.G., Latour, A., Nguyen, M.S., Audoly, L., Coffman, T.M., Koller, B.H. Nat. Med. (2002) [Pubmed]
  8. Site-directed mutagenesis of the conserved tyrosine 151 of human placental NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase yields a catalytically inactive enzyme. Ensor, C.M., Tai, H.H. Biochem. Biophys. Res. Commun. (1991) [Pubmed]
  9. Regulation of synthesis and activity of NAD(+)-dependent 15-hydroxy-prostaglandin dehydrogenase (15-PGDH) by dexamethasone and phorbol ester in human erythroleukemia (HEL) cells. Xun, C.Q., Ensor, C.M., Tai, H.H. Biochem. Biophys. Res. Commun. (1991) [Pubmed]
  10. Expression of the cDNA for NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase as a catalytically active enzyme in Escherichia coli. Ensor, C.M., Tai, H.H. Prostaglandins Leukot. Essent. Fatty Acids (1992) [Pubmed]
  11. Regulation of 15-hydroxy prostaglandin dehydrogenase by corticotrophin-releasing hormone through a calcium-dependent pathway in human chorion trophoblast cells. McKeown, K.J., Challis, J.R. J. Clin. Endocrinol. Metab. (2003) [Pubmed]
  12. Prostaglandin dehydrogenase and the initiation of labor. Challis, J.R., Patel, F.A., Pomini, F. Journal of perinatal medicine. (1999) [Pubmed]
  13. 15-Hydroxyprostaglandin dehydrogenase can be induced by dexamethasone and other glucocorticoids at the therapeutic level in A549 human lung adenocarcinoma cells. Tong, M., Tai, H.H. Arch. Biochem. Biophys. (2005) [Pubmed]
  14. IL-4 regulates COX-2 and PGE(2) production in human non-small cell lung cancer. Cui, X., Yang, S.C., Sharma, S., Heuze-Vourc'h, N., Dubinett, S.M. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  15. Prostaglandin catabolizing enzymes. Tai, H.H., Ensor, C.M., Tong, M., Zhou, H., Yan, F. Prostaglandins Other Lipid Mediat. (2002) [Pubmed]
  16. Levels of NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase are reduced in inflammatory bowel disease: evidence for involvement of TNF-alpha. Otani, T., Yamaguchi, K., Scherl, E., Du, B., Tai, H.H., Greifer, M., Petrovic, L., Daikoku, T., Dey, S.K., Subbaramaiah, K., Dannenberg, A.J. Am. J. Physiol. Gastrointest. Liver Physiol. (2006) [Pubmed]
  17. Regulation of prostaglandin availability in human fetal lung by differential localisation of prostaglandin H synthase-1 and prostaglandin dehydrogenase. Conner, C.E., Kelly, R.W., Hume, R. Histochem. Cell Biol. (2001) [Pubmed]
  18. Synergistic induction of the nicotinamide adenine dinucleotide-linked 15-hydroxyprostaglandin dehydrogenase by an androgen and interleukin-6 or forskolin in human prostate cancer cells. Tong, M., Tai, H.H. Endocrinology (2004) [Pubmed]
  19. Kinetics of IL-10-induced gene expression in human macrophages. Antoniv, T.T., Park-Min, K.H., Ivashkiv, L.B. Immunobiology (2005) [Pubmed]
  20. Histone deacetylase inhibitors and transforming growth factor-beta induce 15-hydroxyprostaglandin dehydrogenase expression in human lung adenocarcinoma cells. Tong, M., Ding, Y., Tai, H.H. Biochem. Pharmacol. (2006) [Pubmed]
  21. Cytokeratin 20, AN43, PGDH, and COX-2 expression in transitional and squamous cell carcinoma of the bladder. Gee, J.R., Montoya, R.G., Khaled, H.M., Sabichi, A.L., Grossman, H.B. Urol. Oncol. (2003) [Pubmed]
  22. 15-hydroxyprostaglandin dehydrogenase and cyclooxygenase 2 messenger ribonucleic acid expression and immunohistochemical localization in human cervical tissue during term and preterm labor. Törnblom, S.A., Patel, F.A., Byström, B., Giannoulias, D., Malmström, A., Sennström, M., Lye, S.J., Challis, J.R., Ekman, G. J. Clin. Endocrinol. Metab. (2004) [Pubmed]
  23. Corticotropin-releasing hormone receptor type 1 and type 2 mediate differential effects on 15-hydroxy prostaglandin dehydrogenase expression in cultured human chorion trophoblasts. Gao, L., He, P., Sha, J., Liu, C., Dai, L., Hui, N., Ni, X. Endocrinology (2007) [Pubmed]
  24. Prostaglandin dehydrogenase and prostaglandin levels in periovulatory follicles: implications for control of primate ovulation by prostaglandin E2. Duffy, D.M., Dozier, B.L., Seachord, C.L. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
  25. Mechanism of cortisol/progesterone antagonism in the regulation of 15-hydroxyprostaglandin dehydrogenase activity and messenger ribonucleic acid levels in human chorion and placental trophoblast cells at term. Patel, F.A., Funder, J.W., Challis, J.R. J. Clin. Endocrinol. Metab. (2003) [Pubmed]
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