Cell and Molecular Biology Program, State University of New York Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA.
Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):1918-23. doi: 10.1073/pnas.0909364107. Epub 2010 Jan 11.
The anticancer peptide PNC-27, which contains an HDM-2-binding domain corresponding to residues 12-26 of p53 and a transmembrane-penetrating domain, has been found to kill cancer cells (but not normal cells) by inducing membranolysis. We find that our previously determined 3D structure of the p53 residues of PNC-27 is directly superimposable on the structure for the same residues bound to HDM-2, suggesting that the peptide may target HDM-2 in the membranes of cancer cells. We now find significant levels of HDM-2 in the membranes of a variety of cancer cells but not in the membranes of several untransformed cell lines. In colocalization experiments, we find that PNC-27 binds to cell membrane-bound HDM-2. We further transfected a plasmid expressing full-length HDM-2 with a membrane-localization signal into untransformed MCF-10-2A cells not susceptible to PNC-27 and found that these cells expressing full-length HDM-2 on their cell surface became susceptible to PNC-27. We conclude that PNC-27 targets HDM-2 in the membranes of cancer cells, allowing it to induce membranolysis of these cells selectively.
抗癌肽 PNC-27 含有与 p53 的残基 12-26 对应的 HDM-2 结合域和一个跨膜穿透域，已被发现通过诱导膜溶解来杀死癌细胞（而不是正常细胞）。我们发现，我们之前确定的 PNC-27 的 p53 残基的 3D 结构与与 HDM-2 结合的相同残基的结构完全一致，这表明该肽可能是靶向癌细胞膜中的 HDM-2。我们现在发现，各种癌细胞的膜中存在大量的 HDM-2，但在几种未转化的细胞系的膜中不存在。在共定位实验中，我们发现 PNC-27 与细胞膜结合的 HDM-2 结合。我们进一步将带有膜定位信号的全长 HDM-2 的表达质粒转染到对 PNC-27 不敏感的未转化 MCF-10-2A 细胞中，发现这些细胞表面表达全长 HDM-2 变得对 PNC-27 敏感。我们得出结论，PNC-27 靶向癌细胞膜中的 HDM-2，使其能够选择性地诱导这些细胞的膜溶解。
