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Cyclooxygenase-2 Is Up-Regulated by Interleukin-1ß in Human Colorectal Cancer Cells via Multiple Signaling Pathways¹

Departments of Cancer Biology [W. L., N. R., O. S., C. T., S. W., Y. D. J., F. F., A. T., M. A., M. B-E., G. E. G., L. M. E.] and Surgical Oncology [A. A. P., L. M. E.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030-4009

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-1ß (IL-1ß) mediates COX-2 expression in HT-29 human colon cancer cells. Treatment of HT-29 cells with IL-1ß 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 NH₂-terminal kinase, P38 mitogen-activated protein kinase, and nuclear factor-B (NF-B) signaling pathways blocked the ability of IL-1ß 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-1ß treatment. Electrophoretic mobility shift assay on nuclear extracts demonstrated that IL-1ß induced NF-B DNA binding activity in HT-29 cells, and the activated NF-B complex was eliminated after treatment with an inhibitor of NF-B. Supershift assay indicated that the two NF-B subunits, p65 and p50, were involved in activation of NF-B complex by IL-1ß stimulation. The stability of COX-2 mRNA was not altered by IL-1ß treatment. These data demonstrate that IL-1ß induces COX-2 expression in HT-29 cells through multiple signaling pathways and NF-B.

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