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J. Biol. Chem., Vol. 280, Issue 5, 3217-3223, February 4, 2005

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15-Hydroxyprostaglandin Dehydrogenase Is Down-regulated in Colorectal Cancer^*

Michael G. Backlund, Jason R. Mann¶, Vijaykumar R. Holla, F. Gregory Buchanan, Hsin-Hsiung Tai||, Erik S. Musiek**, Ginger L. Milne**, Sharada Katkuri, and Raymond N. DuBois¶

From the Departments of Medicine, ^¶Cell and Developmental Biology, ^**Pharmacology, and Cancer Biology, Vanderbilt University Medical Center and the Vanderbilt-Ingram Cancer Center, Nashville, Tennessee 37232-6838 and the ^||Department of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky 40536

Prostaglandin E₂ (PGE₂) can stimulate tumor progression by modulating several proneoplastic pathways, including proliferation, angiogenesis, cell migration, invasion, and apoptosis. Although steady-state tissue levels of PGE₂ stem from relative rates of biosynthesis and breakdown, most reports examining PGE₂ have focused solely on the cyclooxygenase-dependent formation of this bioactive lipid. Enzymatic degradation of PGE₂ involves the NAD⁺-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH). The present study examined a range of normal tissues in the human and mouse and found high levels of 15-PGDH in the large intestine. By contrast, the expression of 15-PGDH is decreased in several colorectal carcinoma cell lines and in other human malignancies such as breast and lung carcinomas. Consistent with these findings, we observe diminished 15-Pgdh expression in Apc^Min+/– mouse adenomas. Enzymatic activity of 15-PGDH correlates with expression levels and the genetic disruption of 15-Pgdh completely blocks production of the urinary PGE₂ metabolite. Finally, 15-PGDH expression and activity are significantly down-regulated in human colorectal carcinomas relative to matched normal tissue. In summary, these results suggest a novel tumor suppressive role for 15-PGDH due to loss of expression during colorectal tumor progression.

Received for publication, September 30, 2004 , and in revised form, November 10, 2004.

^* This work was supported in part by United States Public Health Service Grants RO-DK-62112 and PO-CA77839, the T. J. Martell Foundation, and the National Colorectal Cancer Research Alliance. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

Hortense B. Ingram Professor of Molecular Oncology and recipient of National Institutes of Health MERIT Award R37-DK47297. To whom correspondence should be addressed: Vanderbilt-Ingram Cancer Center, 691 Preston Research Bldg., 2300 Pierce Ave., Nashville, TN 37232-6838. Tel.: 615-343-0527; Fax: 615-936-2697; E-mail: raymond.dubois{at}vanderbilt.edu.

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