15-Hydroxyprostaglandin dehydrogenase, a COX-2 oncogene antagonist, is a TGF-β-induced suppressor of human gastrointestinal cancers

Min Yan, Ronald M. Rerko, Petra Platzer, Dawn Dawson, Joseph Willis, Min Tong, Earl Lawrence, James Lutterbaugh, Shilong Lu, James K V Willson, Guangbin Luo, Jack Hensold, Hsin Hsiung Tai, Keith Wilson, Sanford D. Markowitz

Research output: Contribution to journalArticle

193 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)17468-17473
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number50
DOIs
StatePublished - Dec 14 2004

Keywords

  • Colon
  • Gastric

ASJC Scopus subject areas

  • General

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    Yan, M., Rerko, R. M., Platzer, P., Dawson, D., Willis, J., Tong, M., Lawrence, E., Lutterbaugh, J., Lu, S., Willson, J. K. V., Luo, G., Hensold, J., Tai, H. H., Wilson, K., & Markowitz, S. D. (2004). 15-Hydroxyprostaglandin dehydrogenase, a COX-2 oncogene antagonist, is a TGF-β-induced suppressor of human gastrointestinal cancers. Proceedings of the National Academy of Sciences of the United States of America, 101(50), 17468-17473. https://doi.org/10.1073/pnas.0406142101