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.
Highlights
The majority of gastric cancer in the world is diagnosed in East Asia [1], where the standard therapy for advanced gastric cancers remains surgery and chemotherapy
In an attempt to identify potential biomarkers in this setting at the protein level, we previously reported a cell line panel screening system using quantitative protein expression profiling with Reverse-Phase Protein Arrays (RPPAs) [5,6] combined with a cell-based growth assay system based on the concept of NCI-60 cell line screening panel [7,8]
NF-kB localized to the cytoplasm in untreated MKN45, whereas 5-FU treatment caused an increase in NF-kB nuclear localization (Fig. 1E); no increase was observed in the p53 mutant cell lines (Fig. 1F–H)
Summary
The majority of gastric cancer in the world is diagnosed in East Asia [1], where the standard therapy for advanced gastric cancers remains surgery and chemotherapy. Candidate biomarkers were isolated based on correlation coefficients from protein expression and drug sensitivity matrix and further validated using surgically-removed specimens [9]. Based on this approach we identified two biomarkers at the protein level, including NF-kB and JNK, whose levels had good correlation with chemotherapeutic response. In this study we report a potential compensatory role of NF-kB for p53 through analysis of a p53-NF-kB binding polymorphic site, codon 72 of p53 Together, these findings suggest that NF-kB/p53-codon could be a robust biomarker for 5-FU sensitivity
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