Cancer Selectivity of Tetrabranched Neurotensin Peptides Is Generated by Simultaneous Binding to Sulfated Glycosaminoglycans and Protein Receptors
Cancer Selectivity of Tetrabranched Neurotensin Peptides Is Generated by Simultaneous Binding to Sulfated Glycosaminoglycans and Protein Receptors
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DOI：
10.1021/jm400329p
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发表时间：
2013-06-27
影响因子：
7.3
通讯作者：
Bracci, Luisa
中科院分区：
文献类型：
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作者：
Falciani, Chiara;Brunetti, Jlenia;Bracci, Luisa
在以前的论文中，我们证明了含有人神经降压素NT4序列的四分支肽比天然单体类似物更有选择性地结合不同的人类癌细胞和组织。我们在这里表明，NT4肽，相对于天然神经降压素，无论是癌细胞系或人类癌症手术样本的结合率高得多，是由对其他膜受体的选择性开关，这是由不同的人类癌症特异性表达。我们证明，分支结构提供了NT 4与肝素和属于低密度脂蛋白受体（LDLR）家族，已知参与癌症生物学的受体结合的能力。NT4肽中神经降压素序列的系统修饰导致鉴定了多聚体带正电荷的基序，其介导与肝素和内吞受体的相互作用。我们的研究结果为构建具有高度癌症选择性的癌症治疗诊断剂提供了分子基础。
In previous papers we demonstrated that tetrabranched peptides containing the sequence of human neurotensin, NT4, are much more selective than native monomeric analogues for binding to different human cancer cells and tissues. We show here that the much higher binding of NT4 peptides, with respect to native neurotensin, to either cancer cell lines or human cancer surgical samples is generated by a switch in selectivity toward additional membrane receptors, which are specifically expressed by different human cancers. We demonstrate that the branched structure provides NT4 with ability to bind heparin and receptors belonging to the low density lipoprotein receptor (LDLR) family, known to be involved in cancer biology. Systematic modification of neurotensin sequence in NT4 peptides led to identification of a multimeric positively charged motif, which mediates interaction with both heparin and endocytic receptors. Our findings provide the molecular basis for construction of cancer theranostics with high cancer selectivity.