Oncotarget

Research Papers:

Genistein mediates the selective radiosensitizing effect in NSCLC A549 cells via inhibiting methylation of the keap1 gene promoter region

Xiongxiong Liu, Chao Sun, Bingtao Liu, Xiaodong Jin, Ping Li, Xiaogang Zheng, Ting Zhao, Feifei Li and Qiang Li _

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Oncotarget. 2016; 7:27267-27279. https://doi.org/10.18632/oncotarget.8403

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Abstract

Xiongxiong Liu1,2,3, Chao Sun1,2, Bingtao Liu1,2,3,4, Xiaodong Jin1,2,3, Ping Li1,2,3, Xiaogang Zheng1,2,3,4, Ting Zhao1,2,3, Feifei Li1,2,3,4, Qiang Li1,2,3

1Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, China

2Key Laboratory of Heavy Ion Radiation Biology and Medicine, Chinese Academy of Sciences, Lanzhou 730000, China

3Key Laboratory of Basic Research on Heavy Ion Radiation Application in Medicine, Gansu Province, Lanzhou 730000, China

4University of Chinese Academy of Sciences, Beijing 100049, China

Correspondence to:

Qiang Li, e-mail: [email protected]

Keywords: genistein, selective radiosensitivity, Keap1/Nrf2, methylation, oxidative stress

Received: October 25, 2015     Accepted: March 14, 2016     Published: March 26, 2016

ABSTRACT

Non-small cell lung cancer (NSCLC) cells often possess a hypermethylated Keap1 promoter, which decreases Keap1 mRNA and protein expression levels, thus impairing the Nrf2-Keap1 pathway and thereby leading to chemo- or radio-resistance. In this study, we showed that genistein selectively exhibited a radiosensitizing effect on NSCLC A549 cells but not on normal lung fibroblast MRC-5 cells. Genistein caused oxidative stress in A549 cells rather than MRC-5 cells, as determined by the oxidation of the ROS-sensitive probe DCFH-DA and oxidative damage marked by MDA, PCO or 8-OHdG content. In A549 instead of MRC-5 cells, genistein reduced the level of methylation in the Keap1 promoter region, leading to an increased mRNA expression, thus effectively inhibited the transcription of Nrf2 to the nucleus, which suppressed the Nrf2-dependent antioxidant and resulted in the upregulation of ROS. Importantly, when combined with radiation, genistein further increased the ROS levels in A549 cells whereas decreasing the radiation-induced oxidative stress in MRC-5 cells, possibly via increasing the expression levels of Nrf2, GSH and HO-1. Moreover, radiation combined with genistein significantly increased cell apoptosis in A549 but not MRC-5 cells. Together, the results herein show that the intrinsic difference in the redox status of A549 and MRC-5 cells could be the target for genistein to selectively sensitize A549 cells to radiation, thereby leading to an increase in radiosensitivity for A549 cells.


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