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.
Intervention Section, Cell and Cancer Biology Department, Medicine Branch, Division of Clinical Science, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
S H
SH
Hong
F G
FG
Ondrey
I M
IM
Avis
Z
Z
Chen
E
E
Loukinova
P F
PF
Cavanaugh
C
C
Van Waes
J L
JL
Mulshine
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