title: Regulation of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) by non-steroidal anti-inflammatory drugs (NSAIDs).
abstract: NSAIDs are known to be inhibitors of cyclooxygenase-2 (COX-2) accounting for their anti-inflammatory and anti-tumor activities. However, the anti-tumor activity cannot be totally attributed to their COX-2 inhibitory activity as these drugs can also inhibit the growth and tumor formation of COX-2-null cell lines. Several potential targets aside from COX-2 for NSAIDs have been proposed. 15-Hydroxyprostaglandin dehydrogenase (15-PGDH), a key prostaglandin catabolic enzyme, was recently shown to be a tumor suppressor. Effects of NSAIDs on 15-PGDH expression were therefore studied. Flurbiprofen, indomethacin and other NSAIDs stimulated 15-PGDH activity in colon cancer HT29 cells as well as in lung cancer A549 cells and glioblastoma T98G cells. (R)-flurbiprofen and sulindac sulfone, COX-2 inactive analogs, also stimulated 15-PGDH activity indicating induction of 15-PGDH is independent of COX-2 inhibition. Stimulation of 15-PGDH expression and activity by NSAIDs was examined in detail in colon cancer HT29 cells using flurbiprofen as a stimulant. Flurbiprofen stimulated 15-PGDH expression and activity by increasing transcription and translation and by decreasing the turnover of 15-PGDH. Mechanism of stimulation of 15-PGDH expression is not clear. Protease(s) involved in the turnover of 15-PGDH remains to be identified. However, flurbiprofen down-regulated matrix metalloproteinase-9 (MMP-9) which was shown to degrade 15-PGDH, but up-regulated tissue inhibitor of metalloproteinase-1 (TIMP-1), an inhibitor of MMP-9 contributing further to a slower turnover of 15-PGDH. Taken together, NSAIDs may up-regulate 15-PGDH by increasing the protein expression as well as decreasing the turnover of 15-PGDH in cancer cells.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0082, USA. htai1@uky.edu
authors.forename: Hsin-Hsiung
authors.initials: HH
authors.lastname: Tai
authors.forename: Xiuling
authors.initials: X
authors.lastname: Chi
authors.forename: Min
authors.initials: M
authors.lastname: Tong
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000276:immunology / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004789:Enzyme Activation; D005480:Flurbiprofen / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology*; D005909:Glioblastoma / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007213:Indomethacin / Q000494:pharmacology; D007700:Kinetics; D008175:Lung Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013467:Sulindac / Q000031:analogs & derivatives / Q000494:pharmacology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D019715:Tissue Inhibitor of Metalloproteinase-1; D013467:Sulindac; D005480:Flurbiprofen; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D020780:Matrix Metalloproteinase 9; C025463:sulindac sulfone; D007213:Indomethacin