COX-2 inhibitors suppress lung cancer cell growth by inducing p21 via COX-2 independent signals.
Publication/Presentation Date
3-1-2006
Abstract
COX-2 has been implicated in the control of human non-small cell lung carcinoma (NSCLC) cell growth. The mechanisms by which COX-2 exerts its mitogenic effects have not been entirely elucidated, but stimulation of prostaglandin E2 production and alterations in the expression of the cyclin-dependent kinase inhibitor p21(WAF-1/CIP1/MDA-6)(p2i) have been suggested. Here, we demonstrate that two COX-2 inhibitors (NS398 and Nimesulide) inhibit proliferation and induce apoptosis in NSCLC cells, and these effects were associated with induction of p21 mRNA and protein expression. However, the anti-growth effect of the COX-2 inhibitors and their ability to induce p21 were not affected by COX-2 siRNA suggesting that their actions were COX-2 independent. Instead, activation of the MEK-1/Erk pathway was necessary since COX-2 inhibitors stimulated the phosphorylation of ERKs, and their effects were blocked by PD98095, an inhibitor of this pathway. Furthermore, we show that both NS398 and Nimesulide induced p21 gene promoter activity and this was prevented by PD98095. COX-2 inhibitors increased nuclear protein binding to the Spl site in the promoter region of the p21 gene. Consistent with a role for p21, we found that p21 antisense oligonucleotides prevented the effects of COX-2 inhibitors on cell growth. In summary, our results suggest that COX-2 inhibitors suppress NSCLC cell growth by inducing the expression of the p21 gene through MEK-1/ERK signaling and DNA-protein interactions involving Spl. These observations unveil a mechanism for p21 gene regulation by COX-2 inhibitors in lung carcinoma cell growth and this pathway represents a potential target for therapy.
Volume
51
Issue
3
First Page
283
Last Page
296
ISSN
0169-5002
Published In/Presented At
Han, S., & Roman, J. (2006). COX-2 inhibitors suppress lung cancer cell growth by inducing p21 via COX-2 independent signals. Lung cancer (Amsterdam, Netherlands), 51(3), 283–296. https://doi.org/10.1016/j.lungcan.2005.10.015
Disciplines
Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods
PubMedID
16376453
Department(s)
Administration and Leadership
Document Type
Article