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.

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，这与预后不良有关。PCNA 是一种重要的核 DNA 复制和修复蛋白，通过域间连接环调节大量蛋白质。在该区域内，氨基酸 126-133 对癌细胞中 PCNA 的相互作用至关重要。在这里，我们研究了诱饵细胞穿透肽 R9-caPeptide 的能力，它模拟 PCNA 的域间连接器环区域以破坏胰腺癌细胞中的 PCNA-蛋白质相互作用。我们的数据表明，R9-caPeptide 通过抑制 DNA 复制叉进展和 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。总体而言，这些研究为针对胰腺癌 PCNA 的新型治疗策略奠定了基础。