The cyclin-dependent kinase 2 inhibitor down-regulates interleukin-1beta-mediated induction of cyclooxygenase-2 expression in human lung carcinoma cells.

Abstract

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 G(1) to S phase. In this study, we furnish several lines of evidence that show a functional role for the CDK2 in interleukin-1beta (IL-1beta)-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-1beta-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-1beta-induced COX-2 expression. Third, results from in vitro kinase assays clearly show that IL-1beta induces CDK2 activity in H358 cells and this activity is significantly inhibited by BMS-387032. Moreover, CDK2 inhibition blocks IL-1beta-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-1beta-induced signaling events, such as p38 mitogen-activated protein kinase, phosphorylated stress-activated protein kinase/c-Jun NH(2)-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-1beta-induced COX-2 expression and prostaglandin E(2) synthesis and might represent a novel target for BMS-387032.

• Authors: Partha Mukhopadhyay, M Aktar Ali, Animesh Nandi, Peter Carreon, Hak Choy, Debabrata Saha
• Journal: Cancer research (Cancer Res) Vol. 66 Issue 3 Pg. 1758-66 (Feb 01 2006) ISSN: 0008-5472 [Print] United States
• PMID: 16452236 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• CCAAT-Enhancer-Binding Proteins
• Interleukin-1
• N-(5-(((5-(1,1-dimethylethyl)-2-oxazolyl)methyl)thio)-2-thiazolyl)-4-piperidinecarboxamide
• Oxazoles
• RNA, Messenger
• RNA, Small Interfering
• Thiazoles
• Cyclooxygenase 2
• CDK2 protein, human
• Cyclin-Dependent Kinase 2
• Dinoprostone

Topics

• CCAAT-Enhancer-Binding Proteins (metabolism)
• Carcinoma, Non-Small-Cell Lung (drug therapy, enzymology, genetics)
• Cell Line, Tumor
• Cyclin-Dependent Kinase 2 (antagonists & inhibitors, biosynthesis, genetics)
• Cyclooxygenase 2 (biosynthesis, genetics)
• Dinoprostone (antagonists & inhibitors, biosynthesis)
• Down-Regulation (drug effects)
• Enzyme Induction (drug effects)
• Gene Expression Regulation, Enzymologic
• Gene Expression Regulation, Neoplastic
• Humans
• Interleukin-1 (antagonists & inhibitors, pharmacology)
• Lung Neoplasms (drug therapy, enzymology, genetics)
• Oxazoles (pharmacology)
• Promoter Regions, Genetic (drug effects)
• RNA, Messenger (antagonists & inhibitors, biosynthesis, genetics)
• RNA, Small Interfering (genetics)
• Signal Transduction (drug effects)
• Thiazoles (pharmacology)
• Transcription, Genetic (drug effects)
• Transfection