Preferential induction of necrosis in human breast cancer cells by a p53 peptide derived from the MDM2 binding site.
Do-TN; Rosal-RV; Drew-L; Raffo-AJ; Michl-J; Pincus-MR; Friedman-FK; Petrylak-DP; Cassai-N; Szmulewicz-J; Sidhu-G; Fine-RL; Brandt-Rauf-PW
Oncogene 2003 Mar; 22(10):1431-1444
p53 is the most frequently altered gene in human cancer and therefore represents an ideal target for cancer therapy. Several amino terminal p53-derived synthetic peptides were tested for their antiproliferative effects on breast cancer cell lines MDA-MB-468 (mutant p53), MCF-7 (overexpressed wild-type p53), and MDA-MB-157 (null p53). p53(15)Ant peptide representing the majority of the mouse double minute clone 2 binding site on p53 (amino acids 12-26) fused to the Drosophila carrier protein Antennapedia was the most effective. p53(15)Ant peptide induced rapid, nonapoptotic cell death resembling necrosis in all breast cancer cells; however, minimal cytotoxicity was observed in the nonmalignant breast epithelial cells MCF-10-2A and MCF-10F. Bioinformatic/biophysical analysis utilizing hydrophobic moment and secondary structure predictions as well as circular dichroism spectroscopy revealed an alpha-helical hydrophobic peptide structure with membrane disruptive potential. Based on these findings, p53(15)Ant peptide may be a novel peptide cancer therapeutic because it induces necrotic cell death and not apoptosis, which is uncommon in traditional cancer therapy.
Cancer; Breast-cancer; Genes; Peptides; Cytotoxicity; Cell-cultures;
Author Keywords: breast cancer; p53; MDM2; necrosis
Department of Environmental Health Sciences, The Mailman School of Public Health, Columbia University, New York, New York