Regional differences in prostaglandin E₂ metabolism in human colorectal cancer liver metastases.

Abstract

BACKGROUND:

Prostaglandin (PG) E2 plays a critical role in colorectal cancer (CRC) progression, including epithelial-mesenchymal transition (EMT). Activity of the rate-limiting enzyme for PGE2 catabolism (15-hydroxyprostaglandin dehydrogenase [15-PGDH]) is dependent on availability of NAD+. We tested the hypothesis that there is intra-tumoral variability in PGE2 content, as well as in levels and activity of 15-PGDH, in human CRC liver metastases (CRCLM). To understand possible underlying mechanisms, we investigated the relationship between hypoxia, 15-PGDH and PGE2 in human CRC cells in vitro.

METHODS:

Tissue from the periphery and centre of 20 human CRCLM was analysed for PGE2 levels, 15-PGDH and cyclooxygenase (COX)-2 expression, 15-PGDH activity, and NAD+/NADH levels. EMT of LIM1863 human CRC cells was induced by transforming growth factor (TGF) β.

RESULTS:

PGE2 levels were significantly higher in the centre of CRCLM compared with peripheral tissue (P = 0.04). There were increased levels of 15-PGDH protein in the centre of CRCLM associated with reduced 15-PGDH activity and low NAD+/NADH levels. There was no significant heterogeneity in COX-2 protein expression. NAD+ availability controlled 15-PGDH activity in human CRC cells in vitro. Hypoxia induced 15-PGDH expression in human CRC cells and promoted EMT, in a similar manner to PGE2. Combined 15-PGDH expression and loss of membranous E-cadherin (EMT biomarker) were present in the centre of human CRCLM in vivo.

CONCLUSIONS:

There is significant intra-tumoral heterogeneity in PGE2 content, 15-PGDH activity and NAD+ availability in human CRCLM. Tumour micro-environment (including hypoxia)-driven differences in PGE2 metabolism should be targeted for novel treatment of advanced CRC.

• Authors: Alastair L Young, Claire R Chalmers, Gillian Hawcroft, Sarah L Perry, Darren Treanor, Giles J Toogood, Pamela F Jones, Mark A Hull
• Journal: BMC cancer (BMC Cancer) Vol. 13 Pg. 92 (Feb 26 2013) ISSN: 1471-2407 [Electronic] England
• PMID: 23442768 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Neoplasm Proteins
• Transforming Growth Factor beta
• Hydroxyprostaglandin Dehydrogenases
• 15-hydroxyprostaglandin dehydrogenase
• Dinoprostone

Topics

• Cell Hypoxia
• Colorectal Neoplasms (pathology)
• Dinoprostone (metabolism)
• Epithelial-Mesenchymal Transition (drug effects)
• Humans
• Hydroxyprostaglandin Dehydrogenases (metabolism)
• Immunohistochemistry
• Liver Neoplasms (metabolism, secondary)
• Microarray Analysis
• Neoplasm Proteins (metabolism)
• Transforming Growth Factor beta (pharmacology)
• Tumor Cells, Cultured
• Tumor Microenvironment