ENZYMES IN EICOSANOID METABOLISM

Summary

Principal Investigator: Hsin Hsiung Tai
Abstract: Prostaglandins and hydroxy fatty acids are a family of biologically potent eicosanoids derived from arachidonic acid. These substances are rapidly catabolized and either inactivated or activated further. Prostaglandins are catabolized first by NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH) followed by delta13-15-ketoprostaglandin reductase (13-PGR) resulting in inactive metabolites. Cloning, characterization and structure and activity relationship at 15-PGDH have been extensively studied. However, regulation of the 15-PGDH gene expression has not been explored in any detail. We have cloned the genomic DNA of mouse 15-PGDH gene and have sequenced the 5?-flanking region. We plan to identify specific regulatory elements involved in gene expression, induced by PMA and dexamethosone and to elucidate the signal transduction pathway of androgen activated 15-PGDH expression. We have also cloned and expressed the cDNA of porcine lung 13-PGR in an active form. We propose to identify the binding domains of NADPH and 15-ketoprostaglandins of 13-PGR by photoaffinity labeling studies and to elucidate the structure and function of the enzyme by site-directed mutagenesis. Finally, we propose to purify and characterize a novel 5-hydroxyeicosanoid dehydrogenase (5-HEDH) which generates a powerful activator of leukocytes, 5-KETE, from 5-HETE. The results of this research program should provide a molecular basis of how the expression of 15-PGDH is regulated and a molecular basis of catalysis of 13-PGR. 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.
Funding Period: 1992-08-01 - 2006-07-31
more information: NIH RePORT

Top Publications

  1. ncbi Prostaglandin catabolic enzymes as tumor suppressors
    Hsin Hsiung Tai
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA
    Cancer Metastasis Rev 30:409-17. 2011
  2. ncbi Thromboxane receptor alpha mediates tumor growth and angiogenesis via induction of vascular endothelial growth factor expression in human lung cancer cells
    Jingyan Wei
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536 0082, USA
    Lung Cancer 69:26-32. 2010
  3. pmc Restoration of leukotriene B(4)-12-hydroxydehydrogenase/15- oxo-prostaglandin 13-reductase (LTBDH/PGR) expression inhibits lung cancer growth in vitro and in vivo
    Yuhua Zhao
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536 0082, United States
    Lung Cancer 68:161-9. 2010
  4. ncbi 15-Hydroxyprostaglandin dehydrogenase suppresses K-RasV12-dependent tumor formation in Nu/Nu mice
    Hung Pham
    Department of Medicine, Division of Digestive Diseases, University of California, Los Angeles, California, USA
    Mol Carcinog 47:466-77. 2008
  5. ncbi Activation of extracellular signal-regulated kinase by 12-hydroxyheptadecatrienoic acid in prostate cancer PC3 cells
    Xiuling Li
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536 0082, USA
    Arch Biochem Biophys 467:20-30. 2007
  6. pmc Preterm birth without progesterone withdrawal in 15-hydroxyprostaglandin dehydrogenase hypomorphic mice
    Jeffrey D Roizen
    Washington University School of Medicine, St Louis, Missouri 63110, USA
    Mol Endocrinol 22:105-12. 2008
  7. pmc Activation of thromboxane receptor alpha induces expression of cyclooxygenase-2 through multiple signaling pathways in A549 human lung adenocarcinoma cells
    Jingyan Wei
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536 0082, United States
    Biochem Pharmacol 74:787-800. 2007
  8. ncbi Inhibition of epidermal growth factor receptor signaling elevates 15-hydroxyprostaglandin dehydrogenase in non-small-cell lung cancer
    Li Yang
    Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA
    Cancer Res 67:5587-93. 2007
  9. pmc 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and lung cancer
    Hsin Hsiung Tai
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536 0082, USA
    Prostaglandins Other Lipid Mediat 83:203-8. 2007
  10. ncbi 15-hydroxyprostaglandin dehydrogenase is a tumor suppressor of human breast cancer
    Ido Wolf
    Division of Hematology Oncology, Cedars Sinai Medical Center, University of California at Los Angeles School of Medicine, Los Angeles, CA 90048, USA
    Cancer Res 66:7818-23. 2006

Scientific Experts

  • Ido Wolf
  • Hsin Hsiung Tai
  • Min Tong
  • Jingyan Wei
  • Weili Yan
  • Yunfei Ding
  • Xiuling Li
  • Hoon Cho
  • Yuhua Zhao
  • Jeffrey D Roizen
  • Hung Pham
  • Li Yang
  • Chang Guo Zhan
  • Adel Hamza
  • Chu Chun Weng
  • Lee W Slice
  • Romina Vincenti
  • Minoru Asada
  • Benny Chong
  • Louis J Muglia
  • Guido Eibl
  • David H Johnson
  • Dean Billheimer
  • Adriana Gonzalez
  • Raymond DuBois
  • David P Carbone
  • Takefumi Kikuchi
  • Rut Porta
  • Marta Guix
  • Carlos L Arteaga
  • Kyung Ho Park
  • Wen Chang Chang
  • Joseph M Amann
  • Daquan Gao
  • Lingyu Huang
  • Jeffrey A Moscow
  • Shuqian Liu

Detail Information

Publications19

  1. ncbi Prostaglandin catabolic enzymes as tumor suppressors
    Hsin Hsiung Tai
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA
    Cancer Metastasis Rev 30:409-17. 2011
    ..Future directions of research on these prostaglandin catabolic enzymes as tumor suppressors are also discussed...
  2. ncbi Thromboxane receptor alpha mediates tumor growth and angiogenesis via induction of vascular endothelial growth factor expression in human lung cancer cells
    Jingyan Wei
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536 0082, USA
    Lung Cancer 69:26-32. 2010
    ..However, PI 3-kinase and protein kinase C had minimal contribution. These results indicate that activation of the TPalpha induces the expression of VEGF through multiple signaling pathways...
  3. pmc Restoration of leukotriene B(4)-12-hydroxydehydrogenase/15- oxo-prostaglandin 13-reductase (LTBDH/PGR) expression inhibits lung cancer growth in vitro and in vivo
    Yuhua Zhao
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536 0082, United States
    Lung Cancer 68:161-9. 2010
    ..This study indicates that restoration of LTBDH/PGR expression is effective in preventing lung cancer growth in vitro and in vivo...
  4. ncbi 15-Hydroxyprostaglandin dehydrogenase suppresses K-RasV12-dependent tumor formation in Nu/Nu mice
    Hung Pham
    Department of Medicine, Division of Digestive Diseases, University of California, Los Angeles, California, USA
    Mol Carcinog 47:466-77. 2008
    ..Based on these data, we conclude that PGDH expression suppresses K-Ras(V12)-mediated tumorigenesis in intestinal epithelial cells...
  5. ncbi Activation of extracellular signal-regulated kinase by 12-hydroxyheptadecatrienoic acid in prostate cancer PC3 cells
    Xiuling Li
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536 0082, USA
    Arch Biochem Biophys 467:20-30. 2007
    ..Our results suggest that increased expression of thromboxane synthase as seen in prostate tumor may stimulate tumorigenesis as a consequence of concurrent increased synthesis of two fatty acids capable of activating ERKs...
  6. pmc Preterm birth without progesterone withdrawal in 15-hydroxyprostaglandin dehydrogenase hypomorphic mice
    Jeffrey D Roizen
    Washington University School of Medicine, St Louis, Missouri 63110, USA
    Mol Endocrinol 22:105-12. 2008
    ..Thus, endocrine control of labor has the capacity to plastically adapt to changes in genetically determined prostaglandin signals...
  7. pmc Activation of thromboxane receptor alpha induces expression of cyclooxygenase-2 through multiple signaling pathways in A549 human lung adenocarcinoma cells
    Jingyan Wei
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536 0082, United States
    Biochem Pharmacol 74:787-800. 2007
    ..These results indicate that I-BOP-induced COX-2 expression through multiple signaling pathways...
  8. ncbi Inhibition of epidermal growth factor receptor signaling elevates 15-hydroxyprostaglandin dehydrogenase in non-small-cell lung cancer
    Li Yang
    Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA
    Cancer Res 67:5587-93. 2007
    ..This effect is reversible in a subset of NSCLC upon treatment with an EGFR TKI...
  9. pmc 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and lung cancer
    Hsin Hsiung Tai
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536 0082, USA
    Prostaglandins Other Lipid Mediat 83:203-8. 2007
    ..These results suggest that tumor suppressive action of these agents may, in part, be related to their ability to induce 15-PGDH expression...
  10. ncbi 15-hydroxyprostaglandin dehydrogenase is a tumor suppressor of human breast cancer
    Ido Wolf
    Division of Hematology Oncology, Cedars Sinai Medical Center, University of California at Los Angeles School of Medicine, Los Angeles, CA 90048, USA
    Cancer Res 66:7818-23. 2006
    ..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...
  11. ncbi Histone deacetylase inhibitors and transforming growth factor-beta induce 15-hydroxyprostaglandin dehydrogenase expression in human lung adenocarcinoma cells
    Min Tong
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536 0082, USA
    Biochem Pharmacol 72:701-9. 2006
    ..Together, our results indicate that 15-PGDH is one of the target genes that HDAC inhibitors and TGF-beta may induce to exhibit tumor suppressive effects...
  12. ncbi Role of glutamine 148 of human 15-hydroxyprostaglandin dehydrogenase in catalytic oxidation of prostaglandin E2
    Hoon Cho
    Polymer Science Engineering, Chosun University, Gwangju 501 579, Republic of Korea
    Bioorg Med Chem 14:6486-91. 2006
    ..This indicates that the side-chain oxygen or nitrogen atom at position 148 of 15-PGDH plays an important role in anchoring C-15 hydroxyl group of PGE2 through hydrogen bonding for catalytic reaction...
  13. ncbi Reciprocal regulation of cyclooxygenase-2 and 15-hydroxyprostaglandin dehydrogenase expression in A549 human lung adenocarcinoma cells
    Min Tong
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky Lexington, KY 40536 0082, USA
    Carcinogenesis 27:2170-9. 2006
    ..The levels of IL-1beta-induced COX-2 expression appeared to correlate inversely with those of 15-PGDH expression in the cells. These results support the contention that COX-2 and 15-PGDH are regulated reciprocally in A549 cells...
  14. ncbi NAD+-linked 15-hydroxyprostaglandin dehydrogenase: structure and biological functions
    H H Tai
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, 40536 0082, USA
    Curr Pharm Des 12:955-62. 2006
    ..Future investigations in these areas are warranted...
  15. ncbi 14-3-3zeta interacts with human thromboxane receptors and is involved in the agonist-induced activation of the extracellular-signal-regulated kinase
    Weili Yan
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536 0082, USA
    Biochem Pharmacol 71:624-33. 2006
    ....
  16. ncbi Glycogen synthase kinase-3 phosphorylation, T-cell factor signaling activation, and cell morphology change following stimulation of thromboxane receptor alpha
    Weili Yan
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, 40536 0082, USA
    J Pharmacol Exp Ther 317:267-74. 2006
    ..Together, our results showed for the first time TP agonist-induced phosphorylation of GSK-3 and activation of Tcf/Lef signaling leading to cell proliferation and transformation...
  17. ncbi 15-Hydroxyprostaglandin dehydrogenase can be induced by dexamethasone and other glucocorticoids at the therapeutic level in A549 human lung adenocarcinoma cells
    Min Tong
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536 0082, USA
    Arch Biochem Biophys 435:50-5. 2005
    ..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...
  18. ncbi Key NAD+-binding residues in human 15-hydroxyprostaglandin dehydrogenase
    Hoon Cho
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536 0082, USA
    Arch Biochem Biophys 433:447-53. 2005
    ..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...
  19. ncbi NAD+-linked 15-hydroxyprostaglandin dehydrogenase (15-PGDH) behaves as a tumor suppressor in lung cancer
    Yunfei Ding
    Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA
    Carcinogenesis 26:65-72. 2005
    ..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...