Preferential induction of necrosis in human breast cancer cells by a p53 peptide derived from the MDM2 binding site

被引:75
作者
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 [1 ]
机构
[1] Columbia Univ, Dept Environm Hlth Sci, Mailman Sch Publ Hlth, New York, NY 10032 USA
[2] Columbia Univ Coll Phys & Surg, Div Med Oncol, Expt Therapeut Program, New York, NY 10032 USA
[3] Harbor VA Med Ctr, Dept Pathol & Lab Med, Manhasset, NY 10010 USA
[4] Harbor VA Med Ctr, Dept Pathol & Lab Med, Brooklyn, NY 11209 USA
[5] Suny Downstate Med Ctr, Dept Pathol, Brooklyn, NY 11203 USA
[6] NIH, Lab Metab, Bethesda, MD 20892 USA
关键词
breast cancer; p53; MDM2; necrosis;
D O I
10.1038/sj.onc.1206258
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:1431 / 1444
页数:14
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