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§§, and
- Sanford D. Markowitz*,†,¶,¶¶
- Departments of †Medicine, ‡Molecular Biology and Microbiology, ∥Epidemiology and Biostatistics, **Pathology, and ‡‡Genetics and *Ireland Cancer Center, Case Western Reserve University and University Hospitals, Cleveland, OH 44106; ¶Howard Hughes Medical Institute, Cleveland, OH 44106; ††Division of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536; and §§Protein Design Laboratories, Fremont, CA 94555
-
Edited by Peter K. Vogt, The Scripps Research Institute, La Jolla, CA, and approved November 1, 2004 (received for review August 19, 2004)
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.
Footnotes
-
↵ ¶¶ To whom correspondence should be addressed. E-mail: sxm10{at}po.cwru.edu.
-
↵ § M.Y. and R.M.R. contributed equally to this work.
-
This paper was submitted directly (Track II) to the PNAS office.
-
Abbreviations: 15-PGDH, 15-hydroxyprostaglandin dehydrogenase; COX-2, cyclooxygenase 2.
- Copyright © 2004, The National Academy of Sciences
