Long-term use of NSAIDs leads to a 40-50% reduction in risk for colorectal cancer. How do these “anti-inflammatory” drugs act to reduce cancer risk? NSAIDs effectively target inhibition of prostaglandin synthesis by the cyclooxygenase enzymes (COX-1 and COX-2). Prostaglandins, such as PGE2, regulate the expression of several downstream effector genes, some of which regulate pro-inflammatory pathways. These bioactive lipids signal via G protein-coupled receptors (GPCRs), which in turn can transactivate growth factor receptors and regulate cell proliferation, migration, and cell survival. Prostaglandin E2 (PGE2) has been shown to directly activate components of the canonical Wnt signaling system. Additionally, PGE2 can transactivate the epidermal growth factor receptor (EGFR) in colorectal carcinoma cells via a c-Src dependent mechanism that regulates cell proliferation and migration. We found that the pathway which regulates degradation of prostaglandins, namely 15-PGDH is also regulated by EGFR signaling. We investigated the mechanisms by which PGDH is down-regulated in cancer and showed that epidermal growth factor (EGF) represses PGDH expression in colorectal cancer cells. EGFR signaling induces Snail, which represses PGDH transcription. Induction of PGE2 catabolism through inhibition of EGFR signaling blocks cancer growth in vivo. In human colon cancers, elevated Snail expression correlates well with down-regulation of PGDH. These data indicate that PGDH may serve as a tumor suppressor in colorectal cancer and provide a possible COX-2-independent way to target PGE2 to inhibit cancer progression.
Sixth AACR International Conference on Frontiers in Cancer Prevention Research-- Dec 5-8, 2007; Philadelphia, PA