Chondroitin Sulfate as a Molecular Portal That Preferentially Mediates the Apoptotic Killing of Tumor Cells by Penetratin-directed Mitochondria-disrupting Peptides*
Chondroitin Sulfate as a Molecular Portal That Preferentially Mediates the Apoptotic Killing of Tumor Cells by Penetratin-directed Mitochondria-disrupting Peptides*
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DOI：
10.1074/jbc.m109.089417
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发表时间：
2010-05
期刊：
影响因子：
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通讯作者：
Hao Yang;Shan Liu;H. Cai;L. Wan;Sheng-fu Li;Youping Li;Jingqiu Cheng;Xiaofeng Lu
中科院分区：
文献类型：
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作者：
Hao Yang;Shan Liu;H. Cai;L. Wan;Sheng-fu Li;Youping Li;Jingqiu Cheng;Xiaofeng Lu
细胞穿透肽（cell-penetrating peptides，CPPs）作为靶向治疗药物载体的应用受到CPPs不受限制的细胞转位的限制。然而，穿透素（Antp）定向肽（PNC 27和PNC 28）优先诱导肿瘤细胞死亡表明CPP Antp可能有助于这些肽的优先细胞毒性。使用PNC 27作为分子模型，我们构建了三个新的肽（PT，PR 9和PD 3），通过替换前导肽Antp与三个不同的CPP（达特，R9，或DPV 3），分别。PNC 27在肿瘤细胞中的IC 50值比在正常细胞中低2-3倍。然而，所有三种工程肽在肿瘤和正常细胞中表现出相似的细胞毒性作用。另外三种含有前导肽Antp与不同的细胞分裂素破坏肽（KLA-Antp（KGA）、B27-Antp（BA 27）和B28-Antp（BA 28））的嵌合肽优先诱导肿瘤细胞凋亡。这些肽（3-10 μm）在肿瘤细胞中的IC 50值比在正常细胞中低3-6倍。相反，TAT-导向肽（TAT-KLA（TK）、TAT-B27（TB 27）和TAT-B28（TB 28））对肿瘤和正常细胞都具有细胞毒性。这些数据表明，前导肽Antp有助于Antp定向肽的优先细胞毒性。此外，Antp定向肽结合硫酸软骨素（CS），并且内源性CS的去除降低了Antp定向肽在肿瘤细胞中的细胞毒性作用。CS在肿瘤细胞中的过表达与Antp导向肽的细胞进入和细胞毒性正相关。这些结果表明，CS在肿瘤细胞中的过表达是介导Antp定向肽的优先细胞毒性的重要分子门户。
The use of cell-penetrating peptides (CPPs) as drug carriers for targeted therapy is limited by the unrestricted cellular translocation of CPPs. The preferential induction of tumor cell death by penetratin (Antp)-directed peptides (PNC27 and PNC28), however, suggests that the CPP Antp may contribute to the preferential cytotoxicity of these peptides. Using PNC27 as a molecular model, we constructed three novel peptides (PT, PR9, and PD3) by replacing the leader peptide Antp with one of three distinct CPPs (TAT, R9, or DPV3), respectively. The IC50 values of PNC27 in tumor cells were 2–3 times lower than in normal cells. However, all three engineered peptides demonstrated similar cytotoxic effects in tumor and normal cells. Another three chimeric peptides containing the leader peptide Antp with different mitochondria-disrupting peptides (KLA-Antp (KGA), B27-Antp (BA27), and B28-Antp (BA28)), preferentially induced apoptosis in tumor cells. The IC50 values of these peptides (3–10 μm) were 3–6 times lower in tumor cells than in normal cells. In contrast, TAT-directed peptides (TAT-KLA (TK), TAT-B27 (TB27), and TAT-B28 (TB28)), were cytotoxic to both tumor and normal cells. These data demonstrate that the leader peptide Antp contributes to the preferential cytotoxicity of Antp-directed peptides. Furthermore, Antp-directed peptides bind chondroitin sulfate (CS), and the removal of endogenous CS reduces the cytotoxic effects of Antp-directed peptides in tumor cells. The overexpression of CS in tumor cells is positively correlated to the cell entry and cytotoxicity of Antp- directed peptides. These results suggest that CS overexpression in tumor cells is an important molecular portal that mediates the preferential cytotoxicity of Antp-directed peptides.