Effect of PPAR activators on cytokine-stimulated cyclooxygenase-2 expression in human colorectal carcinoma cells.
Cyclooxygenase-2 (COX-2) expression is up-regulated in colorectal cancer tissue. Peroxisome proliferator-activated receptors (PPARs) are expressed in human colorectal tissue and activation of PPARs can alter COX-2 expression. In macrophages, activation of PPARs down-regulates COX-2 expression. We examined the effect of PPARalpha and PPARgamma ligands on untreated and TNF-alpha-induced COX-2 expression in the human colorectal epithelial cell line HT-29. The expression of PPARalpha and PPARgamma was confirmed in these cells. TNF-alpha, an inflammatory cytokine, increased COX-2 expression via the NFkappaB pathway. In the absence of TNF-alpha, WY14643 (PPARalpha activator) caused an increase, while BRL49653 (PPARgamma activator) did not alter COX-2 expression. When HT-29 cells were incubated with TNF-alpha and WY14643, a further increase in COX-2 expression was detected. Incubation with TNF-alpha and BRL49653 caused an additional twofold increase in COX-2 expression. Our results suggest that both PPARalpha signaling and TNF-alpha signaling increase COX-2 expression by independent pathways, while PPARgamma stimulates COX-2 expression by up-regulation of the TNF-alpha pathway.
Ikawa
H
H
Eicosanoid Biochemistry Section, Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, 111 T W. Alexander Drive, Research Triangle Park, North Carolina, 27709, USA.
Kameda
H
H
Kamitani
H
H
Baek
S J
SJ
Nixon
J B
JB
Hsi
L C
LC
Eling
T E
TE
D000230:Adenocarcinoma / Q000201:enzymology*; D015179:Colorectal Neoplasms / Q000201:enzymology*; D051546:Cyclooxygenase 2; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D019073:HT29 Cells; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis* / Q000235:genetics; D008024:Ligands; D008565:Membrane Proteins; D008954:Models, Biological; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology; D020239:Receptor Cross-Talk; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D000077154:Rosiglitazone; D015398:Signal Transduction; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D007527:Isoenzymes; D008024:Ligands; D008565:Membrane Proteins; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000077154:Rosiglitazone; C006253:pirinixic acid; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases