Abstract
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.
MeSH terms
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Animals
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Antibodies / immunology
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Antibodies / pharmacology
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Arachidonic Acid / metabolism
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Cell Division / drug effects
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Clinical Trials, Phase II as Topic
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Culture Media, Conditioned / metabolism
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Culture Media, Conditioned / pharmacology
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Cyclooxygenase Inhibitors / pharmacology
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DNA-Binding Proteins / metabolism
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Dinoprostone / metabolism
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Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
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Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
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HL-60 Cells
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Humans
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Inflammation / metabolism*
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Interleukin-1 / metabolism
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Interleukin-1 / pharmacology
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Interleukin-6 / antagonists & inhibitors
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Interleukin-6 / immunology
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Interleukin-6 / metabolism*
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Interleukin-6 / pharmacology
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Interleukin-8 / metabolism
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Interleukin-8 / pharmacology
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / metabolism
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Ketorolac / pharmacology
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Mice
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Mice, Inbred BALB C
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Models, Biological
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Oropharyngeal Neoplasms / enzymology*
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Oropharyngeal Neoplasms / metabolism*
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Oropharyngeal Neoplasms / pathology
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Paracrine Communication / drug effects
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Prostaglandin-Endoperoxide Synthases / metabolism*
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptors, Interleukin-6 / metabolism
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STAT3 Transcription Factor
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Signal Transduction / drug effects
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Tetradecanoylphorbol Acetate / pharmacology
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Trans-Activators / metabolism
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Tumor Cells, Cultured
Substances
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Antibodies
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Culture Media, Conditioned
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Cyclooxygenase Inhibitors
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DNA-Binding Proteins
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Interleukin-1
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Interleukin-6
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Interleukin-8
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Isoenzymes
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RNA, Messenger
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Receptors, Interleukin-6
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STAT3 Transcription Factor
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STAT3 protein, human
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Stat3 protein, mouse
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Trans-Activators
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Arachidonic Acid
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Granulocyte-Macrophage Colony-Stimulating Factor
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Prostaglandin-Endoperoxide Synthases
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Dinoprostone
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Tetradecanoylphorbol Acetate
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Ketorolac