Cyclooxygenase regulates human oropharyngeal carcinomas via the proinflammatory cytokine IL-6: a general role for inflammation?
High levels of prostaglandins are produced in human oropharyngeal carcinoma (OPC). Five human OPC cell lines tested expressed both isoforms of cyclooxygenases (COX). The pan-COX inhibitor ketorolac continuously and significantly decreased PGE(2) production and IL-6 and IL-8 levels in all OPC cell lines tested, but did not affect IL-1alpha, GM-CSF levels, or in vitro tumor cell growth. In contrast, ketorolac reduced OPC growth in vivo. The OPC cell lines used express the IL-6 receptor, and IL-6 stimulation of these cells causes transduction to occur via STAT3 pathway activation. Coincubation with OPC cell lines with conditioned medium from a TPA-exposed HL-60 cells stimulated growth proportional to the IL-6 levels measured in the conditioned medium. This growth effect was specifically inhibited by anti-IL-6 antibody. These results are consistent with cytokine products of inflammatory cells having paracrine growth effects on OPC. If chronic inflammation plays a role in promoting the development of OPC, this mechanism may also apply to other epithelial tumor systems modulated by COX activity.
Hong
S H
SH
Intervention Section, Cell and Cancer Biology Department, Medicine Branch, Division of Clinical Science, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Ondrey
F G
FG
Avis
I M
IM
Chen
Z
Z
Loukinova
E
E
Cavanaugh
P F
PF
Van Waes
C
C
Mulshine
J L
JL
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D016718:Arachidonic Acid / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D017322:Clinical Trials, Phase II as Topic; D017077:Culture Media, Conditioned / Q000378:metabolism / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D007375:Interleukin-1 / Q000378:metabolism / Q000494:pharmacology; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D016209:Interleukin-8 / Q000378:metabolism / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D020910:Ketorolac / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D009959:Oropharyngeal Neoplasms / Q000201:enzymology* / Q000378:metabolism* / Q000473:pathology; D019899:Paracrine Communication / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015534:Trans-Activators / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000093242:Interleukin-6 Inhibitors
D000906:Antibodies; D016718:Arachidonic Acid; D017077:Culture Media, Conditioned; D016861:Cyclooxygenase Inhibitors; D004268:DNA-Binding Proteins; D015232:Dinoprostone; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D007375:Interleukin-1; D015850:Interleukin-6; D016209:Interleukin-8; D007527:Isoenzymes; D020910:Ketorolac; D011451:Prostaglandin-Endoperoxide Synthases; D012333:RNA, Messenger; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; D013755:Tetradecanoylphorbol Acetate; D015534:Trans-Activators; D000093242:Interleukin-6 Inhibitors; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse