Proceedings of the National Academy of Sciences - PNAS, 2004-12, Vol.101 (50), p.17468-17473
2004
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- Autor(en) / Beteiligte
- Titel
- 15-Hydroxyprostaglandin Dehydrogenase, a COX-2 Oncogene Antagonist, Is a TGF-β-Induced Suppressor of Human Gastrointestinal Cancers
- Ist Teil von
- Proceedings of the National Academy of Sciences - PNAS, 2004-12, Vol.101 (50), p.17468-17473
- Ort / Verlag
- United States: National Academy of Sciences
- Erscheinungsjahr
- 2004
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Marked increased expression of cyclooxygenase 2 (COX-2), a prostaglandin-synthesizing enzyme that is pharmacologically inhibited by nonsteroid anti-inflammatory-type drugs, is a major early oncogenic event in the genesis of human colon neoplasia. We report that, in addition to inducing expression of COX-2, colon cancers further target the prostaglandin biogenesis pathway by ubiquitously abrogating expression of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a prostaglandin-degrading enzyme that physiologically antagonizes COX-2. We find that 15-PGDH transcript and protein are both highly expressed by normal colonic epithelia but are nearly undetectable in colon cancers. 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. In interrogating the mechanism for 15-PGDH expression loss in colon cancer, we determined that colonic 15-PGDH expression is directly controlled and strongly induced by activation of the TGF-β tumor suppressor pathway. These findings thus delineate an enzymatic pathway that induces colon cancer suppression, a pathway that is activated by TGF-β and mediated by 15-PGDH.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0027-8424eISSN: 1091-6490DOI: 10.1073/pnas.0406142101Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_536023
- Format
- –
- Schlagworte
- Antibodies, Biological Sciences, Cancer, Cell culture techniques, Cell growth, Cell lines, Cell Proliferation - drug effects, Cells, Cultured, Colon, Colonic Neoplasms - enzymology, Colonic Neoplasms - genetics, Colonic Neoplasms - metabolism, Colonic Neoplasms - pathology, Colorectal cancer, Cyclooxygenase 2, Enzymes, Epithelial cells, Gastrointestinal diseases, Gene induction, Humans, Hydroxyprostaglandin Dehydrogenases - genetics, Hydroxyprostaglandin Dehydrogenases - metabolism, Immunohistochemistry, Intestinal Mucosa - enzymology, Intestinal Mucosa - metabolism, Isoenzymes - antagonists & inhibitors, Isoenzymes - metabolism, Kinetics, Medical research, Membrane Proteins, Polymerase chain reaction, Prostaglandin-Endoperoxide Synthases - metabolism, Prostaglandins, RNA, Messenger - genetics, Signal Transduction - drug effects, Transforming Growth Factor beta - pharmacology, Tumor Suppressor Proteins - genetics, Tumor Suppressor Proteins - metabolism, Tumors