Cyclooxygenase-2 inhibitor enhances whereas prostaglandin E2 inhibits the production of interferon-induced protein of 10 kDa in epidermoid carcinoma A431.
Interferon-induced protein of 10 kDa (IP-10) induces antitumor immunity. Cyclooxygenase-2 and its metabolite prostaglandin E2 (PGE2) are overexpressed in tumor cells, which may suppress antitumor immunity. We examined the in vitro effects of cyclooxygenase-2 inhibitor NS398 on IP-10 production in human epidermoid carcinoma A431. NS398 enhanced interferon-gamma-induced IP-10 secretion, mRNA expression, and promoter activation in A431, and exogenous PGE2 antagonized the enhancement. Interferon-stimulated response element (ISRE) on IP-10 promoter was responsible for the transcriptional regulation by NS398 and PGE2. NS398 enhanced interferon-gamma-induced transcription through ISRE and binding of signal transducer and activator of transcription 1alpha (STAT1alpha to ISRE in A431, and PGE2 antagonized the enhancement. NS398 enhanced interferon-gamma-induced tyrosine phosphorylation of STAT1alpha, Janus tyrosine kinase 1, and Janus tyrosine kinase 2, and PGE2 antagonized the enhancement. PGE2-mediated suppression of IP-10 synthesis was counteracted by adenylate cyclase inhibitor SQ22536 and protein kinase A inhibitor H-89, and PGE2 receptor EP4 antagonist AH23848B. AH23848B, SQ22536, and H-89 counteracted the PGE2-mediated suppression of ISRE-dependent transcription, STAT1alpha binding to ISRE, and tyrosine phosphorylation of STAT1alpha, Janus tyrosine kinase 1, and Janus tyrosine kinase 2. PGE2 increased intracellular cAMP level and protein kinase A activity in A431 pretreated with NS398, and AH23848B blocked the effects of PGE2. These results suggest that A431-derived PGE2 may generate cAMP signal via EP4 in A431, which may activate protein kinase A, and may resultantly inhibit interferon-gamma-induced STAT1alpha activation and IP-10 synthesis. The results also suggest that NS398 may restore IP-10 synthesis by preventing PGE2 production in A431 and thus may be therapeutically useful for skin cancer.
Kanda
Naoko
N
Department of Dermatology, Teikyo University, School of Medicine, Tokyo, Japan. nmk@med.teikyo-u.ac.jp
Watanabe
Shinichi
S
D002294:Carcinoma, Squamous Cell; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000096:biosynthesis*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D050832:Interferon-Stimulated Gene Factor 3; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D008565:Membrane Proteins; D009578:Nitrobenzenes / Q000494:pharmacology; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000032:analysis; D018078:Receptors, Prostaglandin E / Q000235:genetics / Q000378:metabolism; D020218:Response Elements; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms; D013449:Sulfonamides / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism
D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D050832:Interferon-Stimulated Gene Factor 3; D007527:Isoenzymes; D008565:Membrane Proteins; D009578:Nitrobenzenes; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D018078:Receptors, Prostaglandin E; D013449:Sulfonamides; D014157:Transcription Factors; C079868:gamma interferon activation factor; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D014443:Tyrosine; D000242:Cyclic AMP; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507924:JAK2 protein, human; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D017868:Cyclic AMP-Dependent Protein Kinases; D015232:Dinoprostone