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NF-kappaB inhibition by an adenovirus expressed aptamer sensitizes TNFalpha-induced apoptosis

Jing Mi1, Xiuwu Zhang, Yingmiao Liu

  • 1Department of Surgery, Duke University Medical Center, Box 2633, MSRB Building, Durham, NC 27710, USA.

Biochemical and Biophysical Research Communications
|June 15, 2007
PubMed

Insights

Inhibiting nuclear factor-kappa B (NF-kappaB) with an RNA aptamer sensitizes cancer and endothelial cells to tumor necrosis factor-alpha (TNFalpha)-induced apoptosis. This approach offers new therapeutic strategies for inflammatory diseases and cancers.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Oncology

Background:

  • Prolonged nuclear factor-kappa B (NF-kappaB) activation is implicated in chronic inflammatory diseases and cancer development.
  • NF-kappaB activation is a key mechanism that confers resistance to tumor necrosis factor-alpha (TNFalpha)-induced apoptosis.

Purpose of the Study:

  • To investigate if inhibiting NF-kappaB can sensitize tumor and endothelial cells to TNFalpha-induced apoptosis.
  • To develop a novel adenoviral vector for targeted NF-kappaB inhibition.

Main Methods:

  • Development of an adenoviral vector (Ad-A-p50) using an H1 RNA polymerase III promoter to express an RNA aptamer.
  • Selective inhibition of NF-kappaB activation in the nucleus.
  • Assessment of apoptosis induction in human lung adenocarcinoma cells (A549) and human umbilical vein endothelial cells (HUVEC) treated with TNFalpha.

Main Results:

  • Ad-A-p50 selectively inhibited NF-kappaB activation in A549 and HUVEC cells.
  • NF-kappaB inhibition sensitized these cells to TNFalpha-induced apoptosis.
  • Apoptosis sensitization occurred via multiple NF-kappaB-regulated pathways, including Bcl-XL, HIF-1alpha, and VEGF.
  • A novel mechanism of HIF-1alpha regulation by NF-kappaB in normoxia was identified.

Conclusions:

  • RNA aptamer-mediated inhibition of NF-kappaB effectively sensitizes cancer and endothelial cells to TNFalpha-induced apoptosis.
  • This strategy presents a promising therapeutic avenue for treating inflammatory conditions and cancers.
  • The study reveals a new regulatory link between NF-kappaB and HIF-1alpha under normoxic conditions.

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