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

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 kB (NF-kB) plays an essential role in preventing apoptotic cell death. In this study, to better understand the mechanism reponsible for the p53-mediated apoptosis, the eect of wild-type p53 (wt-p53) gene transfer on nuclear expression of NF-kB was determined in human colon cancer cell lines. A Western blot analysis of nuclear extracts demonstrated that NF-kB 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 IkBa as well as its binding ability to NF-kB, thus markedly reducing the amount of NF-kB that translocated to the nucleus. The decrease in nuclear NF-kB protein correlated with the decreased NF-kB constitutive activity measured by electrophoretic mobility shift assay. Furthermore, parental cells transfected with NF-kB were better protected from cell death induced by the wt-p53 gene transfer. We also found that the wtp53 gene transfer was synergistic with aspirin (acetylsalicylic acid) in inhibiting NF-kB constitutive activity, resulting in enhanced apoptotic cell death. These results suggest that the inhibition of NF-kB activity is a plausible mechanism for apoptosis induced by the wt-p53 gene transfer in human colon cancer cells and that anti-NF-kB reagent aspirin could make these cells more susceptible to apoptosis. Oncogene (2000) 19, 726 ± 736.

Facilitation of adenoviral wild-type p53-induced apoptotic cell death by overexpression of p33ING1 in T.Tn human esophageal carcinoma cells

“…Similar Ad-p53-induced decreases in p65 and p50 were also reported by Shao et al (2000). However, the decrease in p65 was observed in both parent T.Tn and TnG-4 cells, and also detected in control Ad-LZ-infected cells ( Figure 5d).…”

“…Down-regulation of NF-kB p65 and p50 by p53 was recently shown by Shao et al (2000). The expression of NF-kB p65 increased gradually up to 8 h after infection and thereafter decreased (Figure 5d).…”

Id-1 expression promotes cell survival through activation of NF-κB signalling pathway in prostate cancer cells

“…It was reported that NFkB is a competitor of p53 during apoptosis thus promoting cell survival (Pise-Masison et al, 2000;Shao et al, 2000). In the present study, we found that after exposure to TNFa, although increased p53 was found in all of the cell lines regardless of Id-1 levels (Figure 2a), Bax levels were much higher in the controls.…”

“…In the present study, we found that after exposure to TNFa, although increased p53 was found in all of the cell lines regardless of Id-1 levels (Figure 2a), Bax levels were much higher in the controls. Since Bax has been shown to be directly regulated by p53 during apoptosis (Gupta et al, 2002), it is possible that the Id-1-induced NF-kB activation is able to block the p53-induced Bax expression in LNCaP cells as previously suggested (Pise-Masison et al, 2000;Shao et al, 2000). Another possible explanation for NF-kB-induced antiapoptosis effect is the induction of Bcl-xL ( Figure 3c).…”

“…In addition, the transcription activity of NF-kB is also regulated in response to oncogenic stimulations such as serine/threonine kinase Akt and protein kinase A (Zhong et al, 1998;Madrid et al, 2000). Few studies have also demonstrated that there is a cross-competition between NF-kB and p53, a major proapoptotic protein (Pise-Masison et al, 2000; Shao et al, 2000). Activation of NF-kB has been shown to induce expression of antiapoptotic proteins such as Bcl-xL, which suppresses apoptosis through regulation of caspase activity therefore protecting cells from undergoing apoptosis (Wang et al, 1998;Wu et al, 1998).…”