This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Mukhopadhyay, P. Articles by Saha, D. Search for Related Content PubMed PubMed Citation Articles by Mukhopadhyay, P. Articles by Saha, D.

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)