Colonic 15-PGDH levels are stable across distance and time and are not perturbed by aspirin intervention.

Abstract

BACKGROUND AND AIMS:

15-Hydroxprostaglandin dehydrogenase (15-PGDH) mediates a colon neoplasia suppressor pathway, acting through metabolic antagonism of cyclooxygenase-mediated colon carcinogenesis. To determine whether the colon tumor prevention activity of 15-PGDH acts as a constant or variable effect among individuals, we determined whether 15-PGDH levels remain stable over subsite and time in the human colon, determined the extent of differences in 15-PGDH levels between different individuals, and determined whether 15-PGDH modulation mediates any part of the anti-colon tumor effect of aspirin.

METHODS:

Using real-time PCR, we measured 15-PGDH mRNA to determine the correlation of 15-PGDH level in replicate colon biopsies, in biopsies from throughout the length of the colon, in repeat biopsies taken 4 months apart, and in paired biopsies of individuals taken before and after aspirin treatment, and by Western-blot for 15-PGDH protein in mice.

RESULTS:

Colonic 15-PGDH levels varied 4.4-fold across the human population. Within individuals, 15-PGDH levels proved highly reproducible (r=0.81 in duplicate biopsies) and stable along the length of the colon, with average 15-PGDH levels deviating by only 17% from rectum to cecum. An individual's 15-PGDH levels are also highly stable over time, with a median coefficient of variation over a 4-month interval of only 12%. Last, colonic 15-PGDH levels proved resistant to alteration by aspirin, with only a 10% difference in 15-PGDH levels measured before and after aspirin treatment.

CONCLUSIONS:

15-PGDH levels vary across the population in a stable and reproducible manner, and are resistant to alteration by aspirin. 15-PGDH represents an independent target for modulation by candidate colon tumor chemopreventive agents.

• Authors: Stephen P Fink, Dong-Hoon Yang, Jill S Barnholtz-Sloan, Yeon-Mi Ryu, Debra Mikkola, John D Potter, Johanna W Lampe, Sanford D Markowitz, Seung-Jae Myung
• Journal: Digestive diseases and sciences (Dig Dis Sci) Vol. 58 Issue 9 Pg. 2615-22 (Sep 2013) ISSN: 1573-2568 [Electronic] United States
• PMID: 23625286 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• RNA, Messenger
• Receptors, Transforming Growth Factor beta
• Hydroxyprostaglandin Dehydrogenases
• 15-hydroxyprostaglandin dehydrogenase
• Cyclooxygenase 1
• Cyclooxygenase 2
• PTGS1 protein, human
• PTGS2 protein, human
• Protein Serine-Threonine Kinases
• Receptor, Transforming Growth Factor-beta Type II
• Aspirin

Topics

• Animals
• Aspirin (pharmacology, therapeutic use)
• Chemoprevention
• Colon (drug effects, enzymology)
• Colonic Neoplasms (prevention & control)
• Cyclooxygenase 1 (metabolism)
• Cyclooxygenase 2 (metabolism)
• Female
• Humans
• Hydroxyprostaglandin Dehydrogenases (metabolism)
• Male
• Protein Serine-Threonine Kinases (metabolism)
• RNA, Messenger (metabolism)
• Receptor, Transforming Growth Factor-beta Type II
• Receptors, Transforming Growth Factor beta (metabolism)
• Rectum (enzymology)