title: HGF/Met signalling promotes PGE(2) biogenesis via regulation of COX-2 and 15-PGDH expression in colorectal cancer cells.
abstract: Evidence points towards a pivotal role for cyclooxygenase (COX)-2 in promoting colorectal tumorigenesis through increasing prostaglandin E(2) (PGE(2)) levels. PGE(2) signalling is closely associated with the survival, proliferation and invasion of colorectal cancer cells. Recently, a reduction in PGE(2) inactivation, a process mediated by the nicotinamide adenine dinucleotide (NAD+)-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH), has also been shown to promote tumoral PGE(2) 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 PGE(2) 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 PGE(2) release. Furthermore, inhibition of COX-2 impeded the growth-promoting effects of HGF, suggesting that the COX-2/PGE(2) pathway is an important mediator of HGF/Met signalling. These data reveal a critical role for HGF/Met signalling in promoting PGE(2) biogenesis in colorectal cancer cells. Targeting the crosstalk between these two important pathways may be useful for therapeutic treatment of colorectal cancer.
authors.affiliation: Cancer Research UK Colorectal Tumour Biology Group, Department of Cellular and Molecular Medicine, School of Medical Sciences, University of Bristol, University Walk, Bristol, UK.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Moore
authors.forename: Alexander
authors.initials: A
authors.lastname: Greenhough
authors.forename: Heather R
authors.initials: HR
authors.lastname: Roberts
authors.forename: Diane J
authors.initials: DJ
authors.lastname: Hicks
authors.forename: Helena A
authors.initials: HA
authors.lastname: Patsos
authors.forename: Ann C
authors.initials: AC
authors.lastname: Williams
authors.forename: Christos
authors.initials: C
authors.lastname: Paraskeva
mesh_terms: D000236:Adenoma / Q000235:genetics*; D000818:Animals; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000628:therapy; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism; D015232:Dinoprostone / Q000096:biosynthesis; D015536:Down-Regulation; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D019859:Proto-Oncogene Proteins c-met; D017978:Receptors, Growth Factor / Q000502:physiology*; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; D051546:Cyclooxygenase 2; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D015232:Dinoprostone