Jakobsen Ann-Katrine, Lauridsen Kristina Lystlund, Samuel Evelyn Benuja, Proszek Joanna, Knudsen Birgitta Ruth, Hager Henrik, Stougaard Magnus
Department of Pathology, Aarhus University Hospital, Denmark.
Department of Molecular Biology and Genetics, Aarhus University, Denmark; Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Denmark.
Exp Mol Pathol. 2015 Aug;99(1):56-64. doi: 10.1016/j.yexmp.2015.05.006. Epub 2015 May 16.
Topoisomerase I (TOP1) regulates DNA topology during replication and transcription whereas tyrosyl-DNA phosphodiesterase 1 (TDP1) is involved in the repair of several types of DNA damages, including damages from defective TOP1 catalysis. TOP1 is the target of chemotherapeutic drugs of the camptothecin family (CPT). TDP1 has in cell line based assays been shown to counteract the effect of CPT. We have quantified the enzymatic activities of TOP1 and TDP1 in paired (tumor and adjacent non-tumor) samples from non-small cell lung cancer (NSCLC) patients and show that in NSCLC TOP1 and TDP1 activities are significantly upregulated in the tumor tissue. Furthermore, we found a positive correlation between the TDP1 activity and the tumor percentage (TOP1 activity did not correlate with the tumor percentage) as well as between the activities of TOP1 and TDP1 both within the tumor and the non-tumor group. That TDP1 activity was upregulated in all tumor samples and correlated with the tumor percentage suggest that it must play a highly important function in NSCLC. This could be to protect against TOP1 mediated DNA damage as the activity of TOP1 likewise was upregulated in the majority of tumor samples and correlated positively to the TDP1 activity. Regardless, the finding that the TOP1 and TDP1 activities are upregulated and correlate positively suggests that combinatorial treatment targeting both activities could be advantageous in NSCLC.
拓扑异构酶I（TOP1）在复制和转录过程中调节DNA拓扑结构，而酪氨酰-DNA磷酸二酯酶1（TDP1）参与多种类型DNA损伤的修复，包括由有缺陷的TOP1催化引起的损伤。TOP1是喜树碱家族（CPT）化疗药物的靶点。在基于细胞系的实验中，TDP1已被证明可抵消CPT的作用。我们对非小细胞肺癌（NSCLC）患者的配对（肿瘤和相邻非肿瘤）样本中的TOP1和TDP1酶活性进行了定量分析，结果显示在NSCLC中，肿瘤组织中的TOP1和TDP1活性显著上调。此外，我们发现TDP1活性与肿瘤百分比之间呈正相关（TOP1活性与肿瘤百分比无相关性），并且在肿瘤组和非肿瘤组中TOP1和TDP1的活性之间也呈正相关。TDP1活性在所有肿瘤样本中均上调且与肿瘤百分比相关，这表明它在NSCLC中一定发挥着非常重要的作用。这可能是为了防止TOP1介导的DNA损伤，因为TOP1的活性在大多数肿瘤样本中同样上调且与TDP1活性呈正相关。无论如何，TOP1和TDP1活性上调且呈正相关这一发现表明，针对这两种活性的联合治疗在NSCLC中可能具有优势。
