F1012-2 Induced ROS-Mediated DNA Damage Response through Activation of MAPK Pathway in Triple-Negative Breast Cancer.
F1012-2 Induced ROS-Mediated DNA Damage Response through Activation of MAPK Pathway in Triple-Negative Breast Cancer.
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F1012-2 在三阴性乳腺癌中通过激活 MAPK 途径诱导 ROS 介导的 DNA 损伤反应
DOI：
10.1155/2021/6650045
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发表时间：
2021
影响因子：
--
通讯作者：
Zhao H
中科院分区：
文献类型：
--
作者：
Dai L;Tian S;Zhang J;Lu M;Zhu J;Zhao H
F1012-2是从中草药野马追（Eupatorium lindleyanum DC.）对三阴性乳腺癌（TNBC）表现出强烈的作用。在本研究中，我们发现F1012-2有效地抑制细胞的迁移和侵袭检测伤口愈合和transwell实验。为了阐明F1012-2的潜在机制，我们进一步研究了其对TNBC细胞系DNA损伤的影响。通过单细胞凝胶电泳（彗星试验）、免疫荧光和蛋白质印迹分析，我们发现F1012-2处理诱导了显著的DNA链断裂和γ-H2 AX活化。此外，暴露于F1012-2导致活性氧（ROS）的过度产生。NAC处理完全消除ROS，这可能是由于NAC和F1012-2之间的相互作用。进一步的分子机制研究表明，MAPK信号通路参与了F1012-2的抗TNBC作用。用特异性JNK（SP 600125）和ERK（PD 98059）抑制剂预处理可挽救细胞活力的下降，并抑制JNK和ERK磷酸化的表达，而SB 203580则无此作用。最后，在急性毒性实验中，F1012-2处理组未出现明显的中毒症状。体内研究表明，F1012-2显著抑制肿瘤生长并诱导DNA损伤。总之，F1012-2在体内和体外均诱导TNBC的DNA损伤活性，这可能通过ROS积累触发MAPK通路。这些结果表明F1012-2可能是有效的抗TNBC治疗剂。
We have previously reported that F1012-2, a sesquiterpene lactone isolated from the Chinese herbal medicine Eupatorium lindleyanum DC., exhibits strong effects against Triple Negative Breast Cancer (TNBC). In this study, we found F1012-2 effectively inhibited cell migration and invasion detected by wound healing and transwell assays. In order to elucidate the potential mechanisms of F1012-2, we further studied its effect on DNA damage in TNBC cell lines. Using single cell gel electrophoresis (comet assay), immunofluorescence, and western blotting assays, we found that F1012-2 treatment induced significant DNA strand breaks and γ-H2AX activation. Moreover, exposure to F1012-2 led to overproduction of reactive oxygen species (ROS). NAC treatment completely eliminated ROS, which may be due to the interaction between NAC and F1012-2. A further study of the molecular mechanisms demonstrated that the MAPK signaling pathway participated in the anti-TNBC effect of F1012-2. Pretreatment with specific inhibitors targeting JNK (SP600125) and ERK (PD98059) could rescue the decrease in cell viability and inhibit expressions of JNK and ERK phosphorylation, but SB203580 had no effects. Finally, in the acute toxicity experiment, there were no obvious symptoms of poisoning in the F1012-2 treatment group. An in vivo study demonstrated that F1012-2 significantly suppressed the tumor growth and induced DNA damage. In conclusion, the activity of F1012-2-induced DNA damage in TNBC was found in vivo and in vitro, which might trigger the MAPK pathway through ROS accumulation. These results indicate that F1012-2 may be an effective anti-TNBC therapeutic agent.
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影响因子：
4
作者：
Ma M;Bordignon P;Dotto GP;Pelet S
通讯作者：
Pelet S
影响因子：
5.4
作者：
Khalifa, Shaden A. M.;Elias, Nizar;El-Seedi, Hesham R.
通讯作者：
El-Seedi, Hesham R.
影响因子：
5.9
作者：
Han, Hwana;Lim, Joo Weon;Kim, Hyeyoung
通讯作者：
Kim, Hyeyoung
影响因子：
5.6
作者：
Thomford NE;Senthebane DA;Rowe A;Munro D;Seele P;Maroyi A;Dzobo K
通讯作者：
Dzobo K
影响因子：
4.6
作者：
Lenz, Mairin;Krauth-Siegel, R. Luise;Schmidt, Thomas J.
通讯作者：
Schmidt, Thomas J.