Role of 3' repressor sequences of p53 in anti-cancer drug sensitivity of human lung tumor cells.

INTRODUCTION: The C-terminus of p53 and non-coding mRNAs play critical roles in negative regulation. However, their impact on anti-cancer drug sensitivity remains unclear.

METHODS: In this study, we investigated the effects of p53 deleting these sequences on anti-cancer drug sensitivity by drug sensitivity test, flow cytometry, Agilent mRNA expression microarray detection, transplantation tumor in nude mice.

RESULTS: The results showed that the cell line with p53 deleted the C-terminal sequences (p53(del)) was more sensitive to navelbine (NVB) compared to the cell line that carried the full length p53 (p53(wt)). The p53(del) cells was more sensitive to cisplatin (PDD) and 5-fluorouracil (5FU) than p53(wt) cells but there was not significant difference. NVB treatment led to significant G2 arrest and apoptosis in p53(del) cells but not in p53(wt) cells. mRNA expression profile of p53(del) cells indicated that approximately 11% of the 41,000 genes in genome showed differential expression after NVB treatment, among which 2064 genes were up-regulated and 2784 were down-regulated with fold change >2 (P<0.01). Tumor transplantation assay in nude mice showed that the p53 truncation significantly increased tumor sensitivity to NVB compared to the full-length p53, with 99.46% tumor inhibition.

CONCLUSIONS: In summary, deletion of 37 amino acid residues (356-393) and 3' non-coding mRNAs at the C-terminus of p53 selectively increased tumor sensitivity to the mitotic inhibitor NVB.