Liu Wenbiao, Reinmuth Niels, Stoeltzing Oliver, Parikh Alexander A, Tellez Carmen, Williams Simon, Jung Young D, Fan Fan, Takeda Akihiko, Akagi Morihisa, Bar-Eli Menashe, Gallick Gary E, Ellis Lee M
Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030-4009, USA.
Cancer Res. 2003 Jul 1;63(13):3632-6.
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.
在人类结直肠癌中已观察到环氧合酶-2（COX-2）的过表达。人类肿瘤中的COX-2表达可由生长因子、细胞因子、癌基因和其他因素诱导。调节人类结肠癌中COX-2表达的机制尚未完全阐明。我们假设促炎细胞因子白细胞介素-1β（IL-1β）介导HT-29人结肠癌细胞中COX-2的表达。用IL-1β处理HT-29细胞以时间和剂量依赖性方式诱导COX-2 mRNA和蛋白的表达。细胞外信号调节激酶1/2、c-Jun氨基末端激酶、P38丝裂原活化蛋白激酶和核因子-κB（NF-κB）信号通路的抑制剂阻断了IL-1β诱导COX-2 mRNA的能力。相反，渥曼青霉素是蛋白激酶B/Akt上游的磷脂酰肌醇3-激酶抑制剂，在IL-1β处理后导致COX-2 mRNA表达略有增加。对核提取物进行的电泳迁移率变动分析表明，IL-1β诱导HT-29细胞中NF-κB DNA结合活性，在用NF-κB抑制剂处理后，活化的NF-κB复合物消失。超迁移分析表明，两个NF-κB亚基p65和p50参与了IL-1β刺激对NF-κB复合物的激活。IL-1β处理未改变COX-2 mRNA的稳定性。这些数据表明，IL-1β通过多种信号通路和NF-κB诱导HT-29细胞中COX-2的表达。
