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      Regulation of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) by non-steroidal anti-inflammatory drugs (NSAIDs).

      Prostaglandins & other lipid mediators
      Adenocarcinoma, drug therapy, immunology, metabolism, pathology, Animals, Anti-Inflammatory Agents, Non-Steroidal, pharmacology, Cell Line, Tumor, Colonic Neoplasms, Cyclooxygenase 2, Cyclooxygenase Inhibitors, Enzyme Activation, Flurbiprofen, Gene Expression Regulation, Neoplastic, Glioblastoma, Humans, Hydroxyprostaglandin Dehydrogenases, genetics, Indomethacin, Kinetics, Lung Neoplasms, Matrix Metalloproteinase 9, Matrix Metalloproteinase Inhibitors, Mice, Signal Transduction, Sulindac, analogs & derivatives, Tissue Inhibitor of Metalloproteinase-1, agonists, Up-Regulation

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          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. Copyright © 2011 Elsevier Inc. All rights reserved.

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