NF-kappaB inhibition by an adenovirus expressed aptamer sensitizes TNFalpha-induced apoptosis.
Prolonged activation of NF-kappaB is involved in the pathogenesis of chronic inflammatory diseases and associated cancers. NF-kappaB activation is considered to be a main mechanism opposing TNFalpha-induced apoptosis. We investigated whether inhibition of NF-kappaB could sensitize tumor and endothelial cells to TNFalpha-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-kappaB activation in the nucleus. This event sensitizes human lung adenocarcinoma cells (A549) and human endothelial cells (HUVEC) to TNFalpha-induced apoptosis through the multiple pathways regulated by NF-kappaB, including Bcl-XL, HIF-1alpha, and VEGF. Our findings also suggest a new mechanism of HIF-1alpha regulation by NF-kappaB in the normoxic environment. RNA aptamer inhibition of NF-kappaB offers exciting opportunities for sensitizing inflammatory and tumor cells to TNFalpha-induced apoptosis.
Mi
Jing
J
Department of Surgery, Duke University Medical Center, Box 2633, MSRB Building, Durham, NC 27710, USA.
Zhang
Xiuwu
X
Liu
Yingmiao
Y
Reddy
Srinevas K
SK
Rabbani
Zahid N
ZN
Sullenger
Bruce A
BA
Clary
Bryan M
BM
D000256:Adenoviridae / Q000235:genetics*; D017209:Apoptosis / Q000187:drug effects*; D052157:Aptamers, Nucleotide / Q000235:genetics*; D001483:Base Sequence; D002478:Cells, Cultured; D015536:Down-Regulation; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D052157:Aptamers, Nucleotide; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha