Tumor-treating fields elicit a conditional vulnerability to ionizing radiation via the downregulation of BRCA1 signaling and reduced DNA double-strand break repair capacity in non-small cell lung cancer cell lines.
Tumor-treating fields elicit a conditional vulnerability to ionizing radiation via the downregulation of BRCA1 signaling and reduced DNA double-strand break repair capacity in non-small cell lung cancer cell lines.
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DOI：
10.1038/cddis.2017.136
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发表时间：
2017-03-30
影响因子：
9
通讯作者：
Story MD
中科院分区：
文献类型：
--
作者：
Karanam NK;Srinivasan K;Ding L;Sishc B;Saha D;Story MD
肿瘤治疗场（TTFields）的使用彻底改变了复发性和新诊断的胶质母细胞瘤（GBM）的治疗。TTFields是低强度、中频、交变电场，使用非侵入性阵列施加于肿瘤区域和细胞。TTFields杀死肿瘤细胞的主要机制是破坏有丝分裂。使用五种非小细胞肺癌（NSCLC）细胞系，我们发现这些NSCLC细胞系之间的细胞增殖和细胞杀伤反应不同，与p53状态无关。TTFields治疗增加了G2/M细胞群，伴随着S期细胞减少，随后出现了亚G1细胞群，表明细胞凋亡。评价了TTFields暴露期间基因表达的时间变化，以确定差异TTFields反应背后的分子信号传导变化。差异表达最多的基因与细胞周期和细胞增殖途径有关。然而，在TTFields治疗期间，BRCA 1 DNA损伤反应中发现的基因表达显著下调（P<0.05）。当细胞暴露于TTFields时，DNA双链断裂（DSB）修复病灶增加，染色单体型畸变的出现也是如此，表明细胞死亡的间期机制涉及DNA修复。在电离辐射后立即将细胞暴露于TTFields导致染色单体畸变增加和DNA DSB修复能力降低，这可能是联合用药中观察到的至少部分细胞杀伤增强的原因。这些结果表明，TTFields诱导了一种“BRCAness”状态，导致条件性易感性，从而增强了对电离辐射的敏感性，并为TTFields作为与辐射或其他DNA损伤剂的联合治疗提供了强有力的依据。
The use of tumor-treating fields (TTFields) has revolutionized the treatment of recurrent and newly diagnosed glioblastoma (GBM). TTFields are low-intensity, intermediate frequency, alternating electric fields that are applied to tumor regions and cells using non-invasive arrays. The predominant mechanism by which TTFields are thought to kill tumor cells is the disruption of mitosis. Using five non-small cell lung cancer (NSCLC) cell lines we found that there is a variable response in cell proliferation and cell killing between these NSCLC cell lines that was independent of p53 status. TTFields treatment increased the G2/M population, with a concomitant reduction in S-phase cells followed by the appearance of a sub-G1 population indicative of apoptosis. Temporal changes in gene expression during TTFields exposure was evaluated to identify molecular signaling changes underlying the differential TTFields response. The most differentially expressed genes were associated with the cell cycle and cell proliferation pathways. However, the expression of genes found within the BRCA1 DNA-damage response were significantly downregulated (P<0.05) during TTFields treatment. DNA double-strand break (DSB) repair foci increased when cells were exposed to TTFields as did the appearance of chromatid-type aberrations, suggesting an interphase mechanism responsible for cell death involving DNA repair. Exposing cells to TTFields immediately following ionizing radiation resulted in increased chromatid aberrations and a reduced capacity to repair DNA DSBs, which were likely responsible for at least a portion of the enhanced cell killing seen with the combination. These findings suggest that TTFields induce a state of ‘BRCAness' leading to a conditional susceptibility resulting in enhanced sensitivity to ionizing radiation and provides a strong rationale for the use of TTFields as a combined modality therapy with radiation or other DNA-damaging agents.