Prostaglandin F2alpha-F-prostanoid receptor signaling promotes neutrophil chemotaxis via chemokine (C-X-C motif) ligand 1 in endometrial adenocarcinoma.
The prostaglandin F(2alpha) (PGF(2alpha)) receptor (FP) is elevated in endometrial adenocarcinoma. This study found that PGF(2alpha) 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 PGF(2alpha) 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 PGF(2alpha) 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 PGF(2alpha)-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 PGF(2alpha)-FP pathway that may regulate the inflammatory microenvironment in endometrial adenocarcinoma via neutrophil chemotaxis.
Wallace
Alison E
AE
Medical Research Council Human Reproductive Sciences Unit, Department of Reproductive and Developmental Sciences, The Queen's Medical Research Institute, Edinburgh, United Kingdom.
Sales
Kurt J
KJ
Catalano
Roberto D
RD
Anderson
Richard A
RA
Williams
Alistair R W
AR
Wilson
Martin R
MR
Schwarze
Jurgen
J
Wang
Hongwei
H
Rossi
Adriano G
AG
Jabbour
Henry N
HN
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D054360:Chemokine CXCL1 / Q000235:genetics / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D015237:Dinoprost / Q000494:pharmacology; D016889:Endometrial Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004717:Endometrium / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism*; D023063:Receptors, Interleukin-8B / Q000235:genetics / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014183:Transplantation, Heterologous
D054360:Chemokine CXCL1; D023063:Receptors, Interleukin-8B; D011982:Receptors, Prostaglandin; C034671:prostaglandin F2alpha receptor; D015237:Dinoprost