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, Raymond N. DuBois

Research output: Contribution to journalArticlepeer-review

238 Scopus citations

Abstract

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 ApcMin+/- 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.

Original languageEnglish
Pages (from-to)3217-3223
Number of pages7
JournalJournal of Biological Chemistry
Volume280
Issue number5
DOIs
StatePublished - Feb 4 2005

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