Carcinogenesis Advance Access originally published online on July 28, 2009
Carcinogenesis 2009 30(10):1796-1804; doi:10.1093/carcin/bgp183
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HGF/Met signalling promotes PGE2 biogenesis via regulation of COX-2 and 15-PGDH expression in colorectal cancer cells
Cancer Research UK Colorectal Tumour Biology Group, Department of Cellular and Molecular Medicine, School of Medical Sciences, University of Bristol, University Walk, Bristol, BS8 1TD, UK
* To whom correspondence should be addressed. Tel: +44 (0)1173312072; Fax: +44 (0)1173312091; Email: c.paraskeva{at}bristol.ac.uk
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.
Abbreviations: COX, cyclooxygenase; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; HGF, hepatocyte growth factor; PGE2, prostaglandin E2; 15-PGDH, 15-hydroxyprostaglandin dehydrogenase; MAPK, mitogen-activated protein kinase; mRNA, messenger RNA; MTT, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide; PCR, polymerase chain reaction; siRNA, small interfering RNA
These authors contributed equally to this work. Received April 23, 2009; revised July 2, 2009; accepted July 18, 2009.