Overexpression of the wild-type p53 gene inhibits NF-κB activity and synergizes with aspirin to induce apoptosis in human colon cancer cells

Jianghua Shao, Toshiyoshi Fujiwara, Yoshihiko Kadowaki, Takuya Fukazawa, Toshihiko Waku, Takahiro Itoshima, Tomoki Yamatsuji, Masahiko Nishizaki, Jack A. Roth, Noriaki Tanaka

Research output: Contribution to journalArticle

109 Citations (Scopus)

Abstract

The tumor suppressor gene p53 is a potent transcriptional regulator of genes which are involved in many cellular activities including cell cycle arrest, apoptosis, and angiogenesis. Recent studies have demonstrated that the activation of the transcriptional factor nuclear factor κB (NF-κB) plays an essential role in preventing apoptotic cell death. In this study, to better understand the mechanism reponsible for the p53-mediated apoptosis, the effect of wild-type p53 (wt-p53) gene transfer on nuclear expression of NF-κB was determined in human colon cancer cell lines. A Western blot analysis of nuclear extracts demonstrated that NF-κB protein levels in the nuclei were suppressed by the transient expression of the wt-p53 in a dose-dependent manner. Transduced wt-p53 expression increased the cytoplasmic expression of IκBα as well as its binding ability to NF-κB, thus markedly reducing the amount of NF-KB that translocated to the nucleus. The decrease in nuclear NF-κB protein correlated with the decreased NF-κB constitutive activity measured by electrophoretic mobility shift assay. Furthermore, parental cells transfected with NF-κB were better protected from cell death induced by the wt-p53 gene transfer. We also found that the wt-p53 gene transfer was synergistic with aspirin (acetylsalicylic acid) in inhibiting NF-κB constitutive activity, resulting in enhanced apoptotic cell death. These results suggest that the inhibition of NF-κB activity is a plausible mechanism for apoptosis induced by the wt-p53 gene transfer in human colon cancer cells and that anti-NF-κB reagent aspirin could make these cells more susceptible to apoptosis.

Original languageEnglish
Pages (from-to)726-736
Number of pages11
JournalOncogene
Volume19
Issue number6
DOIs
Publication statusPublished - Feb 10 2000

Keywords

  • Adenovirus vector
  • Aspirin
  • Colon cancer
  • NF-κB
  • p53

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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