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15-Hydroxyprostaglandin dehydrogenase is down-regulated in colorectal cancer.

Backlund MG, Mann JR, Holla VR, Buchanan FG, Tai HH, Musiek ES, Milne GL, Katkuri S, DuBois RN
J Biol Chem. 2005 280 (5): 3217-23

PMID: 15542609 · PMCID: PMC1847633 · DOI:10.1074/jbc.M411221200

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.

MeSH Terms (15)

Animals Colon Colorectal Neoplasms Cyclooxygenase 2 Dinoprostone Gene Expression Regulation, Enzymologic Gene Expression Regulation, Neoplastic Humans Hydroxyprostaglandin Dehydrogenases Membrane Proteins Mice Mice, Inbred C57BL Mice, Mutant Strains Prostaglandin-Endoperoxide Synthases Tumor Cells, Cultured

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