Search

Prostaglandin E(2) (PGE(2)) promotes cancer progression by affecting cell proliferation, apoptosis, angiogenesis, and the immune response. It has been reported that PGE(2) is transported or passes through the cell membrane via prostaglandin-specific transporters including the prostaglandin transporter (PGT, an influx transporter) and the multidrug resistance-associated protein 4 (an efflux transporter). PGT can facilitate the removal of PGE(2) from the extracellular milieu by transporting it into the cell, where 15-hydroxyprostaglandin dehydrogenase (15-PGDH) then oxidizes PGE(2) into 15-keto PGE(2). We previously reported that 15-PGDH expression is reduced in most colorectal cancers, indicating the tumor suppressor role of this gene. In the present study, we show that PGT expression is also decreased (whereas multidrug resistance-associated protein 4 expression is elevated) in human colorectal cancer specimens (compared with expression in normal mucosa) and in colorectal cancer cell lines. Furthermore, we found that PGT expression decreased in premalignant adenomas in APC(min) mice and was partially restored (in human colorectal cancer cell lines) by treatment with a DNA demethylating agent or histone deacetylase inhibitor. Forced PGT overexpression in vitro dose dependently reduced extracellular PGE(2) levels and increased intracellular levels of its catabolic product 15-keto PGE(2). Our collective data suggest that the existing model to explain increased PGE(2) in colorectal neoplasia should be modified to include the novel mechanism of coordinated up- and down-regulation of genes involved in PGE(2) transport.

Prostaglandin E(2) (PGE(2)), a proinflammatory bioactive lipid, promotes cancer progression by modulating proliferation, apoptosis, and angiogenesis. PGE(2) is a downstream product of cyclooxygenase (COX) and is biochemically inactivated by prostaglandin dehydrogenase (PGDH). In the present study, we investigated the mechanisms by which PGDH is down-regulated in cancer. We show that epidermal growth factor (EGF) represses PGDH expression in colorectal cancer cells. EGF receptor (EGFR) signaling induces Snail, which binds conserved E-box elements in the PGDH promoter to repress transcription. Induction of PGE(2) 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 a tumor suppressor function in colorectal cancer and provide a possible COX-2-independent way to target PGE(2) to inhibit cancer progression.

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.

Carcinoma of the colon or rectum represents one of the most common malignancies worldwide with a higher prevalence in industrialized regions. Epidemiologic studies of individuals taking non-steroidal anti-inflammatory drugs (NSAIDs) have shown a significant reduction in colorectal cancer (CRC) mortality compared to those individuals not receiving these agents. NSAIDs inhibit the enzymatic activity of both isoforms of cyclooxygenase (COX-1 and COX-2), while COX-2-selective inhibitors have shown some efficacy in reducing polyp formation. COX-2-derived bioactive lipids, including the primary prostaglandin (PG) generated in colorectal tumors, PGE(2), are known to stimulate cell migration, proliferation and tumor-associated neovascularization while inhibiting cell death. Here we briefly review the role of NSAIDs in preventing CRC, as well as the proposed mechanism by which a COX-2-derived PG, PGE(2), promotes colon cancer.