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The Cyclin-Dependent Kinase 2 Inhibitor Down-regulates Interleukin-1ß-Mediated Induction of Cyclooxygenase-2 Expression in Human Lung Carcinoma Cells

Department of Radiation Oncology, Division of Molecular Radiation Biology, University of Texas Southwestern Medical Center, Dallas, Texas

Requests for reprints: Debabrata Saha, Department of Radiation Oncology, Division of Molecular Radiation Biology, University of Texas Southwestern Medical Center, 2201 Inwood Road, Dallas, TX 75390-9187. Phone: 214-648-7750; Fax: 214-648-5995; E-mail: debabrata.saha{at}utsouthWestern.edu.

Overexpression of cyclooxygenase-2 (COX-2) is frequently observed in several human cancers, including lung, colon, and head and neck. Malignancies are also associated with the dysregulation of cell cycle events and concomitant elevated activity of cyclin-dependent kinases (CDK). CDK2 is a key cell cycle regulatory protein that controls the transition of cells from G₁ to S phase. In this study, we furnish several lines of evidence that show a functional role for the CDK2 in interleukin-1ß (IL-1ß)–induced COX-2 expression in H358 human non–small cell lung carcinoma cell line by blocking CDK2 activity. First, we show that BMS-387032, a potent CDK2 inhibitor, blocks IL-1ß-induced expression as well as steady-state mRNA levels of COX-2. Second, we show that small interfering RNA that abrogates CDK2 expression also blocks IL-1ß-induced COX-2 expression. Third, results from in vitro kinase assays clearly show that IL-1ß induces CDK2 activity in H358 cells and this activity is significantly inhibited by BMS-387032. Moreover, CDK2 inhibition blocks IL-1ß-induced binding to the NF-IL6 element of the COX-2 promoter and inhibits transcription of the COX-2 gene. We also observed that BMS-387032 does not inhibit endogenous expression of COX-2 or prostaglandin synthesis in lung carcinoma cells. Finally, we provide evidence showing that IL-1ß-induced signaling events, such as p38 mitogen-activated protein kinase, phosphorylated stress-activated protein kinase/c-Jun NH₂-terminal kinase, phosphorylated AKT, and phosphorylated extracellular signal-regulated kinase 1/2, are not inhibited by CDK2 inhibitor. Taken together, the data suggest that CDK2 activity may play an important event in the IL-1ß-induced COX-2 expression and prostaglandin E₂ synthesis and might represent a novel target for BMS-387032. (Cancer Res 2006; 66(3): 1758-66)

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