An iASPP-derived short peptide restores p53-mediated cell death in cancers with wild-type p53

Abstract

Background

Inhibitor of apoptosis-stimulating protein of p53 (iASPP) is an evolutionarily conserved p53 inhibitor. Mechanistically, iASPP can accelerate tumorigenesis by inhibiting the transactivation function of p53. Targeting the interaction between iASPP and p53 may be a potential therapy for restoring the activity of p53 in tumors.

Methods

We constructed an iASPP-derived peptide, called A8, that was derived from the C-terminus of iASPP. Here, we transfected A8 into two wild-type (WT) p53 cell lines, U2OS and A549, and then determined the number of apoptotic cells. The mechanism by which A8 affected apoptosis was further examined by immunoprecipitation (IP), Dual-Luciferase reporter assays, and chromatin IP assays. Real-time polymerase chain reaction and western blots were also used to examine the expression levels of apoptosis-related factors.

Results

Our data demonstrate that A8 can increase apoptosis rates in WT p53 cell lines. Functional analysis suggested that A8 restored the transcriptional function and DNA binding activities of p53 toward the Bax and PUMA gene promoters. Moreover, A8 reduced cell proliferation and inhibited tumor growth in xenograft nude mice.

Conclusions

These data provide a new approach for restoring the tumor suppressor function of p53 in cancer cells that express WT p53 and therefore may serve as a novel cancer treatment strategy.