Molecular Decoy to the Y-Box Binding Protein-1 Suppresses the Growth of Breast and Prostate Cancer Cells whilst Sparing Normal Cell Viability
Molecular Decoy to the Y-Box Binding Protein-1 Suppresses the Growth of Breast and Prostate Cancer Cells whilst Sparing Normal Cell Viability
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DOI：
10.1371/journal.pone.0012661
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发表时间：
2010-09-10
期刊：
影响因子：
3.7
通讯作者：
Dunn, Sandra E.
中科院分区：
文献类型：
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作者：
Law, Jennifer H.;Li, Yvonne;Dunn, Sandra E.
Y-box结合蛋白-1（YB-1）是一种致癌转录/翻译因子，通过S102处的磷酸化激活，从而诱导生长促进基因（如EGFR和HER-2）的表达。我们最近通过体外激酶测定说明，YB-1的新肽被丝氨酸/苏氨酸p90 S6激酶RSK-1和RSK-2高度磷酸化，并且在较小程度上被PKC α和AKT磷酸化。在此，我们试图开发这种诱饵细胞渗透肽（CPP）作为癌症治疗剂。基于分子对接，将该9聚体设计为将阻止内源性YB-1 S-102磷酸化的干扰肽。在癌细胞中，CPP阻断P-YB-1（S102）并下调HER-2和EGFR的转录水平和蛋白表达。此外，CPP阻止YB-1在凝胶位移测定中与EGFR启动子结合。值得注意的是，使用CPP，乳腺癌细胞（SUM 149、MDA-MB-453、AU565）和前列腺癌细胞（PC 3、LNCap）的生长被抑制了接近90%。此外，用该肽治疗增强了敏感性，并克服了表达扩增HER-2的细胞对曲妥珠单抗的耐药性。与此相反，CPP对正常永生化乳腺上皮（184 htert）细胞、原代乳腺上皮细胞的生长没有抑制作用，也不抑制造血祖细胞的分化。这些数据共同表明，CPP是一种抑制癌细胞生长同时保留正常细胞的新方法，从而建立了概念验证，即阻断YB-1活化是一种新的癌症治疗方法。
The Y-box binding protein-1 (YB-1) is an oncogenic transcription/translation factor that is activated by phosphorylation at S102 whereby it induces the expression of growth promoting genes such as EGFR and HER-2. We recently illustrated by an in vitro kinase assay that a novel peptide to YB-1 was highly phosphorylated by the serine/threonine p90 S6 kinases RSK-1 and RSK-2, and to a lesser degree PKC alpha and AKT. Herein, we sought to develop this decoy cell permeable peptide (CPP) as a cancer therapeutic. This 9-mer was designed as an interference peptide that would prevent endogenous YB-1 S-102 phosphorylation based on molecular docking. In cancer cells, the CPP blocked P-YB-1(S102) and down-regulated both HER-2 and EGFR transcript level and protein expression. Further, the CPP prevented YB-1 from binding to the EGFR promoter in a gel shift assay. Notably, the growth of breast (SUM149, MDA-MB-453, AU565) and prostate (PC3, LNCap) cancer cells was inhibited by similar to 90% with the CPP. Further, treatment with this peptide enhanced sensitivity and overcame resistance to trastuzumab in cells expressing amplified HER-2. By contrast, the CPP had no inhibitory effect on the growth of normal immortalized breast epithelial (184htert) cells, primary breast epithelial cells, nor did it inhibit differentiation of hematopoietic progenitors. These data collectively suggest that the CPP is a novel approach to suppressing the growth of cancer cells while sparing normal cells and thereby establishes a proof-of-concept that blocking YB-1 activation is a new course of cancer therapeutics.