NF-κB inhibition by an adenovirus expressed aptamer sensitizes TNFα-induced apoptosis

Abstract: Prolonged activation of NF-κB is involved in the pathogenesis of chronic inflammatory diseases and associated cancers. NF-κB activation is considered to be a main mechanism opposing TNFα-induced apoptosis. We investigated whether inhibition of NF-κB could sensitize tumor and endothelial cells to TNFα-induced apoptosis. As such, we developed a novel H1 RNA polymerase III promoter driven adenoviral vector to express an RNA aptamer, Ad-A-p50, which selectively inhibits NF-κB activation in the nucleus. This event sensitizes human lung adenocarcinoma cells (A549) and human endothelial cells (HUVEC) to TNFα-induced apoptosis through the multiple pathways regulated by NF-κB, including Bcl-XL, HIF-1α, and VEGF. Our findings also suggest a new mechanism of HIF-1α regulation by NF-κB in the normoxic environment. RNA aptamer inhibition of NF-κB offers exciting opportunities for sensitizing inflammatory and tumor cells to TNFα-induced apoptosis. [Copyright &y& Elsevier]