HGF/Met signalling promotes PGE2 biogenesis via regulation of COX-2 and 15-PGDH expression in colorectal cancer cells

Moore, Amy E.; Greenhough, Alexander; Roberts, Heather R.; Hicks, Diane J.; Patsos, Helena A.; Williams, Ann C.; Paraskeva, Christos

Abstract

Evidence points towards a pivotal role for cyclooxygenase (COX)-2 in promoting colorectal tumorigenesis through increasing prostaglandin E2 (PGE2) levels. PGE2 signalling is closely associated with the survival, proliferation and invasion of colorectal cancer cells. Recently, a reduction in PGE2 inactivation, a process mediated by the nicotinamide adenine dinucleotide (NAD+)-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH), has also been shown to promote tumoral PGE2 accumulation. The hepatocyte growth factor (HGF) receptor, Met, is frequently over-expressed in colorectal tumours and promotes cancer growth, metastasis and resistance to therapy, although the mechanisms for this have not been fully elucidated. Here, we report that HGF/Met signalling can promote PGE2 biogenesis in colorectal cancer cells via COX-2 up-regulation and 15-PGDH down-regulation at the protein and messenger RNA level. Pharmacological inhibition of MEK and PI3K suggested that both extracellular signal-regulated kinase (ERK) and AKT signalling are required for COX-2 protein up-regulation and 15-PGDH down-regulation downstream of Met. Notably, inhibition of Met with the small molecule inhibitor SU11274 reduced COX-2 expression and increased 15-PGDH expression in high Met-expressing cells. We also show that hypoxia potentiated HGF-driven COX-2 expression and enhanced PGE2 release. Furthermore, inhibition of COX-2 impeded the growth-promoting effects of HGF, suggesting that the COX-2/PGE2 pathway is an important mediator of HGF/Met signalling. These data reveal a critical role for HGF/Met signalling in promoting PGE2 biogenesis in colorectal cancer cells. Targeting the crosstalk between these two important pathways may be useful for therapeutic treatment of colorectal cancer. © The Author 2009. Published by Oxford University Press. All rights reserved.

• Journal Article Type: Article
• Acceptance Date: Jul 18, 2009
• Online Publication Date: Jul 28, 2009
• Publication Date: Oct 20, 2009
• Journal: Carcinogenesis
• Print ISSN: 0143-3334
• Electronic ISSN: 1460-2180
• Publisher: Oxford University Press (OUP)
• Peer Reviewed: Peer Reviewed
• Volume: 30
• Issue: 10
• Pages: 1796-1804
• DOI: https://doi.org/10.1093/carcin/bgp183
• Public URL: https://uwe-repository.worktribe.com/output/994203
• Publisher URL: https://doi.org/10.1093/carcin/bgp183