PDF(Pubmed)
Abstract：
Ionizing radiation (IR) and chemotherapy with DNA-damaging drugs such as cisplatin are vital cancer treatment options. These treatments induce double-strand breaks (DSBs) as cytotoxic DNA damage; thus, the DSB repair activity in each cancer cell significantly influences the efficacy of the treatments. Pancreatic cancers are known to be resistant to these treatments, and the overexpression of MUC1, a member of the glycoprotein mucins, is associated with IR- and chemo-resistance. Therefore, we investigated the impact of MUC1 on DSB repair. This report examined the effect of the overexpression of MUC1 on homologous recombination (HR) and non-homologous end-joining (NHEJ) using cell-based DSB repair assays. In addition, the therapeutic potential of NHEJ inhibitors including HDAC inhibitors was also studied using pancreatic cancer cell lines. The MUC1-overexpression enhances NHEJ, while partially suppressing HR. Also, MUC1-overexpressed cancer cell lines are preferentially killed by a DNA-PK inhibitor and HDAC1/2 inhibitors. Altogether, MUC1 induces metabolic changes that create an imbalance between NHEJ and HR activities, and this imbalance can be a target for selective killing by HDAC inhibitors. This is a novel mechanism of MUC1-mediated IR-resistance and will form the basis for targeting MUC1-overexpressed pancreatic cancer.
摘要：
电离辐射(IR)和使用DNA损伤药物如顺铂的化疗是重要的癌症治疗选择。这些治疗诱导双链断裂（DSB）作为细胞毒性DNA损伤；因此，每个癌细胞中的DSB修复活性显著影响治疗的功效。众所周知，胰腺癌对这些治疗有抵抗力，和MUC1的过表达，MUC1是糖蛋白粘蛋白的成员，与IR和化学抗性有关。因此,我们研究了MUC1对DSB修复的影响。该报告使用基于细胞的DSB修复测定法检查了MUC1过表达对同源重组（HR）和非同源末端连接（NHEJ）的影响。此外,还使用胰腺癌细胞系研究了包括HDAC抑制剂在内的NHEJ抑制剂的治疗潜力.MUC1过表达增强NHEJ，同时部分抑制HR。此外，MUC1过表达的癌细胞系优先被DNA-PK抑制剂和HDAC1/2抑制剂杀死。总之,MUC1诱导代谢变化，造成NHEJ和HR活动之间的不平衡，这种失衡可能是HDAC抑制剂选择性杀伤的目标。这是MUC1介导的IR抗性的新机制,并且将形成靶向MUC1过表达的胰腺癌的基础。
