15-Hydroxyprostaglandin Dehydrogenase Is Down-regulated in Colorectal Cancer

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 exami...

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Bibliographic Details
Published in:The Journal of biological chemistry 2005-02, Vol.280 (5), p.3217-3223
Main Authors: Backlund, Michael G., Mann, Jason R., Holla, Vijaykumar R., Buchanan, F. Gregory, Tai, Hsin-Hsiung, Musiek, Erik S., Milne, Ginger L., Katkuri, Sharada, DuBois, Raymond N.
Format: Article
Language:English
Subjects:
Animals
Colon - enzymology
Colorectal Neoplasms - metabolism
Colorectal Neoplasms - physiopathology
Cyclooxygenase 2
Dinoprostone - metabolism
Gene Expression Regulation, Enzymologic
Gene Expression Regulation, Neoplastic
Humans
Hydroxyprostaglandin Dehydrogenases - genetics
Hydroxyprostaglandin Dehydrogenases - metabolism
Membrane Proteins
Mice
Mice, Inbred C57BL
Mice, Mutant Strains
Prostaglandin-Endoperoxide Synthases - metabolism
Tumor Cells, Cultured
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Summary: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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M411221200