title: Cyclooxygenase-2 is up-regulated by interleukin-1 beta in human colorectal cancer cells via multiple signaling pathways.
abstract: Overexpression of cyclooxygenase-2 (COX-2) has been observed in human colorectal cancer. COX-2 expression in human tumors can be induced by growth factors, cytokines, oncogenes, and other factors. The mechanisms regulating COX-2 expression in human colon cancer have not been completely elucidated. We hypothesized that the proinflammatory cytokine interleukin-1 beta (IL-1 beta) mediates COX-2 expression in HT-29 human colon cancer cells. Treatment of HT-29 cells with IL-1 beta induced expression of COX-2 mRNA and protein in a time- and dose-dependent manner. Inhibitors of the extracellular signal-regulated kinase 1/2, c-Jun NH(2)-terminal kinase, P38 mitogen-activated protein kinase, and nuclear factor-kappa B (NF-kappa B) signaling pathways blocked the ability of IL-1 beta to induce COX-2 mRNA. In contrast, Wortmannin, a phosphoinositide 3-kinase inhibitor upstream of protein kinase B/Akt, led to a slight increase in COX-2 mRNA expression after IL-1 beta treatment. Electrophoretic mobility shift assay on nuclear extracts demonstrated that IL-1 beta induced NF-kappa B DNA binding activity in HT-29 cells, and the activated NF-kappa B complex was eliminated after treatment with an inhibitor of NF-kappa B. Supershift assay indicated that the two NF-kappa B subunits, p65 and p50, were involved in activation of NF-kappa B complex by IL-1 beta stimulation. The stability of COX-2 mRNA was not altered by IL-1 beta treatment. These data demonstrate that IL-1 beta induces COX-2 expression in HT-29 cells through multiple signaling pathways and NF-kappa B.
authors.affiliation: Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030-4009, USA.
authors.forename: Wenbiao
authors.initials: W
authors.lastname: Liu
authors.forename: Niels
authors.initials: N
authors.lastname: Reinmuth
authors.forename: Oliver
authors.initials: O
authors.lastname: Stoeltzing
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Parikh
authors.forename: Carmen
authors.initials: C
authors.lastname: Tellez
authors.forename: Simon
authors.initials: S
authors.lastname: Williams
authors.forename: Young D
authors.initials: YD
authors.lastname: Jung
authors.forename: Fan
authors.initials: F
authors.lastname: Fan
authors.forename: Akihiko
authors.initials: A
authors.lastname: Takeda
authors.forename: Morihisa
authors.initials: M
authors.lastname: Akagi
authors.forename: Menashe
authors.initials: M
authors.lastname: Bar-Eli
authors.forename: Gary E
authors.initials: GE
authors.lastname: Gallick
authors.forename: Lee M
authors.initials: LM
authors.lastname: Ellis
mesh_terms: D003110:Colonic Neoplasms; D051546:Cyclooxygenase 2; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D007527:Isoenzymes / Q000235:genetics*; D008565:Membrane Proteins; D008954:Models, Biological; D016328:NF-kappa B / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects*; D014407:Tumor Cells, Cultured
chemical_list: D007375:Interleukin-1; D007527:Isoenzymes; D008565:Membrane Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases