Proneoplastic effects of PGE2 mediated by EP4 receptor in colorectal cancer.
Authors
Doherty, Glen AByrne, Sinead M
Molloy, Eamonn S
Malhotra, Vikrum
Austin, Sandra C
Kay, Elaine W
Murray, Frank E
Fitzgerald, Desmond J
Affiliation
Molecular Medicine Group, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland. glen_doherty@hotmail.comIssue Date
2009MeSH
Cell Line, TumorCell Membrane
Cell Proliferation
Colorectal Neoplasms
Cyclin-Dependent Kinase Inhibitor p21
Cyclooxygenase 2
Dinoprostone
Flow Cytometry
Gene Expression Regulation, Neoplastic
Humans
Immunohistochemistry
Precancerous Conditions
Receptor, Epidermal Growth Factor
Receptors, Prostaglandin E
Reverse Transcriptase Polymerase Chain Reaction
Metadata
Show full item recordCitation
Proneoplastic effects of PGE2 mediated by EP4 receptor in colorectal cancer. 2009, 9:207 BMC CancerJournal
BMC cancerDOI
10.1186/1471-2407-9-207PubMed ID
19558693Abstract
BACKGROUND: Prostaglandin E2 (PGE2) is the major product of Cyclooxygenase-2 (COX-2) in colorectal cancer (CRC). We aimed to assess PGE2 cell surface receptors (EP 1-4) to examine the mechanisms by which PGE2 regulates tumour progression. METHODS: Gene expression studies were performed by quantitative RT-PCR. Cell cycle was analysed by flow cytometry with cell proliferation quantified by BrdU incorporation measured by enzyme immunoassay. Immunohistochemistry was employed for expression studies on formalin fixed paraffin embedded tumour tissue. RESULTS: EP4 was the most abundant subtype of PGE2 receptor in HT-29 and HCA7 cells (which show COX-2 dependent PGE2 generation) and was consistently the most abundant transcript in human colorectal tumours (n = 8) by qRT-PCR (ANOVA, p = 0.01). G0/G1 cell cycle arrest was observed in HT-29 cells treated with SC-236 5 microM (selective COX-2 inhibitor) for 24 hours (p = 0.02), an effect abrogated by co-incubation with PGE2 (1 microM). G0/G1 arrest was also seen with a specific EP4 receptor antagonist (EP4A, L-161982) (p = 0.01). Treatment of HT-29 cells with either SC-236 or EP4A caused reduction in intracellular cAMP (ANOVA, p = 0.01). Early induction in p21WAF1/CIP1 expression (by qRT-PCR) was seen with EP4A treatment (mean fold increase 4.4, p = 0.04) while other genes remained unchanged. Similar induction in p21WAF1/CIP1 was also seen with PD153025 (1 microM), an EGFR tyrosine kinase inhibitor, suggesting EGFR transactivation by EP4 as a potential mechanism. Additive inhibition of HCA7 proliferation was observed with the combination of SC-236 and neutralising antibody to amphiregulin (AR), a soluble EGFR ligand. Concordance in COX-2 and AR localisation in human colorectal tumours was noted. CONCLUSION: COX-2 regulates cell cycle transition via EP4 receptor and altered p21WAF1/CIP1 expression. EGFR pathways appear important. Specific targeting of the EP4 receptor or downstream targets may offer a safer alternative to COX-2 inhibition in the chemoprevention of CRC.Language
enISSN
1471-2407ae974a485f413a2113503eed53cd6c53
10.1186/1471-2407-9-207
Scopus Count
Collections
Related articles
- Role of prostaglandin E2 receptors in migration of murine and human breast cancer cells.
- Authors: Timoshenko AV, Xu G, Chakrabarti S, Lala PK, Chakraborty C
- Issue date: 2003 Oct 1
- PGE2-induced hypertrophy of cardiac myocytes involves EP4 receptor-dependent activation of p42/44 MAPK and EGFR transactivation.
- Authors: Mendez M, LaPointe MC
- Issue date: 2005 May
- Prostaglandin E2 Promotes Colorectal Cancer Stem Cell Expansion and Metastasis in Mice.
- Authors: Wang D, Fu L, Sun H, Guo L, DuBois RN
- Issue date: 2015 Dec
- Cyclooxygenase-2-dependent prostaglandin E2 down-regulates intercellular adhesion molecule-1 expression via EP2/EP4 receptors in interleukin-1beta-stimulated human gingival fibroblasts.
- Authors: Noguchi K, Iwasaki K, Shitashige M, Endo H, Kondo H, Ishikawa I
- Issue date: 2000 Dec
- Prostaglandin E2-EP4 receptor signalling promotes tumorigenic behaviour of HT-29 human colorectal cancer cells.
- Authors: Hawcroft G, Ko CW, Hull MA
- Issue date: 2007 May 10