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Open Access

EP4-mediated prostanoid signalling promotes oral cancer progression

  • Karen Sapienza1Email author,
  • Stewart Sale2,
  • Angela Hague3,
  • Ian R Hart1,
  • John F Marshall1 and
  • Gareth J Thomas4
BMC Proceedings20104(Suppl 2):P35

Published: 24 September 2010


Oral CancerProstanoidRac1 ActivationPGE2 SynthesisMarked Upregulation

Cyclooxygenase-2 (COX-2) enzyme is upregulated in oral cancer (OSCC), where it catalyses PGE2 synthesis. We have shown previously that PGE2 promotes integrin-dependent OSCC invasion (1). PGE2 has four receptors (EP1-4), each coupled to different intracellular signaling pathways. We therefore investigated the role of EP receptor signaling in the invasive process.

We used immunochemistry and RT-PCR to examine EP receptor expression in OSCC cell lines and OSCC in vivo, and found marked upregulation of EP4. Chemical inhibition or transient knockdown of EP4 in OSCC lines significantly reduced levels of intracellular cyclic AMP (cAMPi), whereas EP4 overexpression increased cAMPi. Using Transwell and organotypic invasion assays, we studied the functional role of EP4. Overexpression of EP4 promoted OSCC invasion, with confocal microscopy revealing that EP4 localized to filopodia, processes associated with cell motility. Conversely, inhibition of either EP4 or cAMPi suppressed invasion. Treatment of cells with the cAMP agonist, forskolin, restored invasion following PGE2 suppression. We identified the GTP-ase, Rac1, as a downstream target of cAMPi, where inhibition of EP4 or cAMPi suppressed Rac1 activation, and RNAi abrogation of Rac1 inhibited invasion.

Our data describe a novel signaling pathway in cancer invasion, and suggest that COX-2/PGE2-dependent OSCC signaling is primarily modulated through the EP4 receptor, leading to increased cAMPi and Rac1 activation. Targeting EP4 may be an important strategy to suppress tumor progression, and may avoid the side-effects associated with systemic administration of COX-2 inhibitors.

Authors’ Affiliations

Centre for Tumour Biology, Institute of Cancer, Barts and the London School of Medicine, London, UK
Cancer Biomarkers and Prevention Group, University of Leicester, Leicester, UK
Department of Oral & Dental Science, University of Bristol, Bristol, UK
Experimental Pathology Group, Cancer Sciences Division, University of Southampton School of Medicine, Southampton, UK


  1. Nystrom ML, McCulloch D, Weinreb PH, Violette SM, Speight PM, Marshall JF, Hart IR, Thomas GJ: Cyclooxygenase-2 inhibition suppresses αvβ6 integrin-dependent oral squamous carcinoma invasion. Cancer Res. 2006, 66: 10833-10842. 10.1158/0008-5472.CAN-06-1640.View ArticlePubMedGoogle Scholar


© Sapienza et al; licensee BioMed Central Ltd. 2010

This article is published under license to BioMed Central Ltd.