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首页> 美国卫生研究院文献>Molecular Pharmacology >A Peptide Mimicking a Region in Proliferating Cell Nuclear Antigen Specific to Key Protein Interactions Is Cytotoxic to Breast Cancer
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A Peptide Mimicking a Region in Proliferating Cell Nuclear Antigen Specific to Key Protein Interactions Is Cytotoxic to Breast Cancer

机译：模仿关键蛋白相互作用特异的增殖细胞核抗原中的一个区域的肽对乳腺癌具有细胞毒性。

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Proliferating cell nuclear antigen (PCNA) is a highly conserved protein necessary for proper component loading during the DNA replication and repair process. Proteins make a connection within the interdomain connector loop of PCNA, and much of the regulation is a result of the inherent competition for this docking site. If this target region of PCNA is modified, the DNA replication and repair process in cancer cells is potentially altered. Exploitation of this cancer-associated region has implications for targeted breast cancer therapy. In the present communication, we characterize a novel peptide (caPeptide) that has been synthesized to mimic the sequence identified as critical to the cancer-associated isoform of PCNA. This peptide is delivered into cells using a nine-arginine linking mechanism, and the resulting peptide (R9-cc-caPeptide) exhibits cytotoxicity in a triple-negative breast cancer cell line, MDA-MB-436, while having less of an effect on the normal counterparts (MCF10A and primary breast epithelial cells). The novel peptide was then evaluated for cytotoxicity using various in vivo techniques, including ATP activity assays, flow cytometry, and clonogenetic assays. This cytotoxicity has been observed in other breast cancer cell lines (MCF7 and HCC1937) and other forms of cancer (pancreatic and lymphoma). R9-cc-caPeptide has also been shown to block the association of PCNA with chromatin. Alanine scanning of the peptide sequence, combined with preliminary in silico modeling, gives insight to the disruptive ability and the molecular mechanism of action of the therapeutic peptide in vivo.
机译：增殖细胞核抗原（PCNA）是在DNA复制和修复过程中正确加载组分所必需的高度保守的蛋白质。蛋白质在PCNA的域间连接器环内建立连接，而许多调控是该对接位点固有竞争的结果。如果PCNA的这个目标区域被修改，则癌细胞中的DNA复制和修复过程可能会发生改变。该癌症相关区域的开发对靶向乳腺癌治疗具有重要意义。在本通讯中，我们表征了一种新型肽（caPeptide），该肽已合成以模拟被鉴定为对PCNA癌相关亚型至关重要的序列。使用九精氨酸连接机制将该肽递送到细胞中，所得肽（R9-cc-caPeptide）在三阴性乳腺癌细胞MDA-MB-436中显示出细胞毒性，而对正常的对应物（MCF10A和原发性乳腺上皮细胞）。然后使用各种体内技术（包括ATP活性测定，流式细胞术和克隆生成测定）评估新型肽的细胞毒性。在其他乳腺癌细胞系（MCF7和HCC1937）和其他形式的癌症（胰腺癌和淋巴瘤）中也观察到了这种细胞毒性。 R9-cc-caPeptide也已显示出可阻断PCNA与染色质的缔合。丙氨酸对肽序列的扫描，结合初步的计算机模拟，可以洞察治疗性肽在体内的破坏能力和分子机制。

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