Molecular Targeting of Cancer-Associated PCNA Interactions in Pancreatic Ductal Adenocarcinoma Using a Cell-Penetrating Peptide.
Molecular Targeting of Cancer-Associated PCNA Interactions in Pancreatic Ductal Adenocarcinoma Using a Cell-Penetrating Peptide.
复制标题
使用细胞穿透肽对胰腺导管腺癌中癌症相关的 PCNA 相互作用进行分子靶向。
DOI：
10.1016/j.omto.2020.03.025
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Raoof,Mustafa
中科院分区：
文献类型：
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作者：
Smith,ShannaJ;Li,CarolineM;Lingeman,RobertG;Hickey,RobertJ;Liu,Yilun;Malkas,LindaH;Raoof,Mustafa
由于缺乏有效的筛查或治疗，胰腺导管腺癌是一种特别难以治疗的癌症。胰腺癌细胞表现出高增殖细胞核抗原（PCNA）表达，与预后不良有关。PCNA是一种重要的核DNA复制和修复蛋白，通过结构域间连接环调节无数蛋白质。在这个区域内，氨基酸126-133对癌细胞中的PCNA相互作用至关重要。在这里，我们研究了一种诱骗细胞穿透肽R9-caPeptide的能力，它模拟PCNA的结构域间连接器环区域，破坏胰腺癌细胞中PCNA-蛋白的相互作用。我们的数据表明，R9-caPeptide通过抑制DNA复制叉的进展和pcna调节的DNA修复，在一组胰腺癌细胞系中引起剂量依赖性毒性，最终导致致命的DNA损伤。总之，这些研究为胰腺癌靶向PCNA的新治疗策略奠定了基础。
Pancreatic ductal adenocarcinoma is a particularly difficult cancer to treat due to a lack of effective screening or treatment. Pancreatic cancer cells exhibit high proliferating cell nuclear antigen (PCNA) expression, which is associated with poor prognosis. PCNA, an important nuclear DNA replication and repair protein, regulates a myriad of proteins via the interdomain connector loop. Within this region, amino acids 126–133 are critical for PCNA interactions in cancer cells. Here, we investigate the ability of a decoy cell-penetrating peptide, R9-caPeptide, that mimics the interdomain connector loop region of PCNA to disrupt PCNA-protein interactions in pancreatic cancer cells. Our data suggest that R9-caPeptide causes dose-dependent toxicity in a panel of pancreatic cancer cell lines by inhibiting DNA replication fork progression and PCNA-regulated DNA repair, ultimately causing lethal DNA damage. Overall, these studies lay the foundation for novel therapeutic strategies that target PCNA in pancreatic cancer.