A Compensatory Role of NF-κB to p53 in Response to 5-FU–Based Chemotherapy for Gastric Cancer Cell Lines

Abstract

Despite of remarkable improvement of postoperative 5-FU–based adjuvant chemotherapy, the relapse rate of gastric cancer patients who undergo curative resection followed by the adjuvant chemotherapy remains substantial. Therefore, it is important to identify prediction markers for the chemotherapeutic efficacy of 5-FU. We recently identified NF-κB as a candidate relapse prediction biomarker in gastric cancer. To evaluate the biological significance of NF-κB in the context of 5-FU–based chemotherapy, we analyzed the NF-κB-dependent biological response upon 5-FU treatment in gastric cancer cell lines. Seven genes induced by 5-FU treatment in an NF-κB-dependent manner were identified, five of which are known p53 targets. Knockdown of RELA, which encodes the p65 subunit of NF-κB, decreased both p53 and p53 target protein levels. In contrast, NF-κB was not affected by TP53 knockdown. We also demonstrated that cell lines bearing Pro/Pro homozygosity in codon72 of p53 exon4, which is important for NF-κB binding to p53, are more resistant to 5-FU than those with Arg/Arg homozygosity. We conclude that NF-κB plays an important role in the response to 5-FU treatment in gastric cancer cell lines, with a possible compensatory function of p53. These results suggest that NF-κB is a potential 5-FU-chemosensitivity prediction marker that may reflect 5-FU-induced stress-response pathways, including p53.

Sumoylation of HDAC2 promotes NF-κB-dependent gene expression

“…We therefore tested for a functional contribution of p53 toward the HDAC2-dependent control of NF-κB. Interestingly, p53 is an NF-κB target [34, 35] and this should result in higher p53 mRNA levels in cells with enhanced NF-κB activity. Indeed, p53 mRNA levels were higher in RKO cells expressing wild-type HDAC2 (Figure 3A).…”

“…T P 53 carries an evolutionary conserved consensus κB-binding site [34, 40]. Accordingly, the expression of TP53 is diminished when NF-κB is blocked [34] and recent data show that a knockdown of p65 decreases p53 protein levels [35]. Many mechanisms including post-transcriptional events regulate p53 protein levels.…”

Helicobacter pylori infection is associated with favorable outcome in advanced gastric cancer patients treated with S‐1 adjuvant chemotherapy

“…In previous studies we investigated gastric cancer cell lines exposed to anticancer agents as a model for assessing relapse suppression with adjuvant chemotherapy . The majority of adjuvant chemotherapy regimens use 5‐FU, which induces both p53 and NF‐κB to activate context‐specific transcriptional machinery in cancer cells in response to DNA damage .…”

“…Use of the S‐1 adjuvant chemotherapy is thought to have led to an increase in the 5‐year overall survival (OS) by approximately 10%, but the relapse rate still remains 30‐40% . We previously identified aberrant nuclear expression of NF‐κB transcription factor and TP53 codon 72 polymorphisms, located in the NF‐κB binding site, as potential biomarkers for 5‐FU sensitivity based on a gastric cancer cell line model for post‐surgical patients treated with S‐1 adjuvant chemotherapy . However, target cells of the adjuvant therapy in patients are anchor‐free or micrometastatic, and therefore an assessment of anti‐tumor ability in vitro may not translate directly to the clinic .…”

“…NF‐κB expression subsequently mediates ectopic expression of activation‐induced cytidine deaminase (AID), which is a nucleotide editing enzyme essential for somatic hypermutation . In fact, 5‐FU‐mediated compensatory induction of p53 and NF‐κB in response to DNA damage has been reported, and therefore we hypothesized that TP53 codon 72 polymorphisms could be surrogate markers of chemotherapeutic resistance in gastric cancer cells . In addition to the involvement of H. pylori in gastric carcinogenesis, the molecular response induced by H. pylori in the gastric mucosa has been hypothesized to be associated with the effects of gastric cancer treatment .…”