Radiosensitization by PARP Inhibition in DNA Repair Proficient and Deficient Tumor Cells: Proliferative Recovery in Senescent Cells.
Radiosensitization by PARP Inhibition in DNA Repair Proficient and Deficient Tumor Cells: Proliferative Recovery in Senescent Cells.
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DOI：
10.1667/rr14202.1
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发表时间：
2016-03
影响因子：
3.4
通讯作者：
Gewirtz DA
中科院分区：
文献类型：
--
作者：
Alotaibi M;Sharma K;Saleh T;Povirk LF;Hendrickson EA;Gewirtz DA
放射疗法仍然是治疗癌症的主要方式。辐射诱导的DNA损伤可以促进细胞凋亡以及自噬和衰老，其中自噬和衰老理论上可以起到延长肿瘤存活的作用。这项工作的主要目的是研究自噬和/或衰老可能允许DNA修复的假设，从而促进肿瘤细胞从辐射诱导的生长停滞和/或细胞死亡中恢复。此外，研究旨在阐明自噬和衰老参与PARP抑制剂的辐射增敏和增殖肿瘤细胞群的重新出现。在这项工作的背景下，辐射诱导的自噬和衰老之间的关系也被确定。使用DNA修复熟练的HCT 116结肠癌细胞和修复缺陷型连接酶IV（-/-）等基因细胞系进行研究。辐射促进了自噬和衰老的平行诱导，这与两种细胞系中持续H2 AX磷酸化的程度密切相关;然而，抑制自噬未能抑制衰老，表明这两种反应是可分离的。辐照导致HCT 116细胞短暂停滞，而Ligase IV（−/−）细胞的停滞时间延长;然而，两种细胞系最终都恢复了增殖功能，这可能反映了DNA修复能力的维持。PARP抑制剂（奥拉帕尼）和（Niraparib）增加了辐射诱导的持续性DNA损伤程度以及自噬和衰老程度;单独辐射或在存在PARP抑制剂的情况下，细胞系均未发生显著凋亡。自噬的抑制未能减弱辐射敏化，表明自噬不参与PARP抑制剂的作用。与单独辐射一样，尽管PARP抑制致敏，但增殖恢复在10-20天内明显。虽然通过PARP抑制来抑制DNA修复最初可能通过促进衰老而使肿瘤细胞对辐射敏感，但这种策略似乎不会干扰增殖恢复，这可能最终导致疾病复发。
Radiotherapy continues to be a primary modality in the treatment of cancer. DNA damage induced by radiation can promote apoptosis as well as both autophagy and senescence, where autophagy and senescence can theoretically function to prolong tumor survival. A primary aim of this work was to investigate the hypothesis that autophagy and/or senescence could be permissive for DNA repair, thereby facilitating tumor cell recovery from radiation-induced growth arrest and/or cell death. In addition, studies were designed to elucidate the involvement of autophagy and senescence in radiation sensitization by PARP inhibitors and the re-emergence of a proliferating tumor cell population. In the context of this work, the relationship between radiation-induced autophagy and senescence was also determined. Studies were performed using DNA repair proficient HCT116 colon carcinoma cells and a repair deficient Ligase IV (−/−) isogenic cell line. Irradiation promoted a parallel induction of autophagy and senescence that was strongly correlated with the extent of persistent H2AX phosphorylation in both cell lines; however inhibition of autophagy failed to suppress senescence, indicating that the two responses were dissociable. Irradiation resulted in a transient arrest in the HCT116 cells while arrest was prolonged in the Ligase IV (−/−) cells; however, both cell lines ultimately recovered proliferative function, which may reflect maintenance of DNA repair capacity. The PARP inhibitors (Olaparib) and (Niraparib) increased the extent of persistent DNA damage induced by radiation as well as the extent of both autophagy and senescence; neither cell line underwent significant apoptosis by radiation alone or in the presence of the PARP inhibitors. Inhibition of autophagy failed to attenuate radiation sensitization, indicating that autophagy was not involved in the action of the PARP inhibitors. As with radiation alone, despite sensitization by PARP inhibition, proliferative recovery was evident within a period of 10–20 days. While inhibition of DNA repair via PARP inhibition may initially sensitize tumor cells to radiation via the promotion of senescence, this strategy does not appear to interfere with proliferative recovery, which could ultimately contribute to disease recurrence.