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Overexpression of p65 attenuates celecoxib-induced cell death in MDA-MB-231 human breast cancer cell line.

Abstract：

BACKGROUND:Celecoxib is a selective cyclooxygenase (COX)-2 inhibitor that has been reported to reduce the risk of breast cancer. In our previous study, celecoxib induced apoptosis and caused cell cycle arrest at the G0/G1 phase in the breast cancer cell line MDA-MB-231, and its effects were mediated by downregulation of NF-κB signaling. The NF-κB p65/RelA subunit may play a role in cell death through the activation of anti-apoptotic target genes including the inhibitor of apoptosis (IAP) and Bcl-2 families, and inhibition of protein kinase B/Akt. The aim of the present study was to investigate p65 as the potential target of celecoxib treatment and determine whether p65 overexpression can override the inhibitory effect of celecoxib on NF-κB activity and affect cell survival. METHODS:The effects of p65 overexpression on celecoxib-inhibited NF-κB transcriptional activity were examined by western blotting, electrophoretic mobility shift assay (EMSA) and luciferase reporter gene assay. Cell viability and cell death were evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) assay, and the levels of cleaved poly(ADP-ribose) polymerase (PARP) and caspase. Anti-apoptotic NF-κB target genes and cell cycle regulators were examined by western blotting to screen for the expression of target genes under direct regulation by p65. RESULTS:Overexpression of p65 increased NF-κB transcriptional activity and interfered with celecoxib-mediated apoptosis as assessed by MTT assay and caspase-3, caspase-9, and PARP expressions. Exogenously overexpressed p65 upregulated NF-κB-responsive genes, including anti-apoptotic genes such as survivin and XIAP, and the cell cycle regulatory gene cyclin D1. However, p65 overexpression did not affect celecoxib-induced p-Akt inactivation, suggesting that celecoxib might have separate molecular mechanisms for regulating Akt signaling independently of its inhibition of NF-κB transcriptional activity. CONCLUSIONS:p65 is a pivotal anti-apoptotic factor that can reverse celecoxib-induced growth inhibition in MDA-MB-231 cells.

journal_name

Cancer Cell Int

journal_title

Cancer cell international

authors

Wang L,Kang F,Li J,Zhang J,Shan B

doi

10.1186/1475-2867-13-14

subject

Has Abstract

pub_date

2013-02-12 00:00:00

pages

issue

issn

1475-2867

pii

1475-2867-13-14

journal_volume

pub_type

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Overexpression of p65 attenuates celecoxib-induced cell death in MDA-MB-231 human breast cancer cell line.