Prostaglandin F₂-F-Prostanoid Receptor Signaling Promotes Neutrophil Chemotaxis via Chemokine (C-X-C Motif) Ligand 1 in Endometrial Adenocarcinoma

¹Medical Research Council Human Reproductive Sciences Unit, Departments of ²Reproductive and Developmental Sciences and ³Pathology, and ⁴Centre for Inflammation Research, The Queen's Medical Research Institute, Edinburgh, United Kingdom

^* To whom correspondence should be addressed. E-mail: H.Jabbour{at}hrsu.mrc.ac.uk.

	Abstract

The prostaglandin F₂ (PGF₂) receptor (FP) is elevated in endometrial adenocarcinoma. This study found that PGF₂ signaling via FP regulates expression of chemokine (C-X-C motif) ligand 1 (CXCL1) in endometrial adenocarcinoma cells. Expression of CXCL1 and its receptor, CXCR2, are elevated in cancer tissue compared with normal endometrium and localized to glandular epithelium, endothelium, and stroma. Treatment of Ishikawa cells stably transfected with the FP receptor (FPS cells) with 100 nmol/L PGF₂ increased CXCL1 promoter activity, mRNA, and protein expression, and these effects were abolished by cotreatment of cells with FP antagonist or chemical inhibitors of Gq, epidermal growth factor receptor, and extracellular signal-regulated kinase. Similarly, CXCL1 was elevated in response to 100 nmol/L PGF₂ in endometrial adenocarcinoma explant tissue. CXCL1 is a potent neutrophil chemoattractant. The expression of CXCR2 colocalized to neutrophils in endometrial adenocarcinoma and increased neutrophils were present in endometrial adenocarcinoma compared with normal endometrium. Conditioned media from PGF₂-treated FPS cells stimulated neutrophil chemotaxis, which could be abolished by CXCL1 protein immunoneutralization of the conditioned media or antagonism of CXCR2. Finally, xenograft tumors in nude mice arising from inoculation with FPS cells showed increased neutrophil infiltration compared with tumors arising from wild-type cells or following treatment of mice bearing FPS tumors with CXCL1-neutralizing antibody. In conclusion, our results show a novel PGF₂-FP pathway that may regulate the inflammatory microenvironment in endometrial adenocarcinoma via neutrophil chemotaxis. [Cancer Res 2009;69(14):OF1–8]

Key Words: Prostaglandin F₂, endometrial cancer, neutrophil, CXCL1, CXCR2