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

Partha Mukhopadhyay, M. Aktar Ali, Animesh Nandi, Peter Carreon, Hak Choy, Debabrata Saha

Research output: Contribution to journalArticle

23 Scopus citations

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 G1 to S phase. In this study, we furnish several lines of evidence that show a functional role for the CDK2 in interleukin-1β (IL-1β)-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-1β-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-1β-induced COX-2 expression. Third, results from in vitro kinase assays clearly show that IL-1β induces CDK2 activity in H358 cells and this activity is significantly inhibited by BMS-387032. Moreover, CDK2 inhibition blocks IL-1β-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-1β-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-1β-induced COX-2 expression and prostaglandin E2 synthesis and might represent a novel target for BMS-387032.

Original languageEnglish (US)
Pages (from-to)1758-1766
Number of pages9
JournalCancer Research
Volume66
Issue number3
DOIs
StatePublished - Feb 1 2006

    Fingerprint

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this