Lung cancer is the leading cause of cancer-related death accounting for more than 1.3 million deaths worldwide annually. Despite advances in treatment, the five-year survival rate is 2% if the cancer has metastasized to other organs. The major cause of poor prognosis of advanced lung cancer is multi-resistance to chemo/radio therapy. Therefore, it is crucial to understand the underlying mechanisms of chemo/radio resistance and develop therapeutic strategies to overcome the resistance. Transcription factor Nrf2 is a key regulator of cytoprotective genes which facilitate cellular defense against harmful insults. We found that Nrf2 and its downstream target NQO1 are highly upregulated in lung cancer patient tumor tissues as well as in lung cancer cell lines compared to adjacent normal tissues or normal cell lines. We hypothesized that the upregulated Nrf2 may be responsible for radio/chemo resistance and malignancy in lung cancer. RNA interference studies showed that knockdown of Nrf2 substantially increased the sensitivity of human lung cancer H460 and A549 cells to radiation-induced cell death. Knockdown of Nrf2 also decreased tumor sphere formation, suggesting its role in cancer stem cell (CSC) regulation which may be responsible for the radioresistance. Analyses of CSC markers including ALDH and Oct4 in control and Nrf2-knockdown H460 and A549 cells support this finding. Together, our results indicate an essential role of Nrf2 in the control and regulation of CSCs and radioresistance. Since CSCs are widely believed to be responsible for cancer chemoresistance and relapse, our novel finding on the role of Nrf2 in radiation resistance may aid in the design of novel therapeutic strategies for resistant cancers.

Citation Format: Xiaoqing He, Alex Chi, Liying Wang, Yon Rojanasakul. Nrf2 confers radioresistance by regulating cancer stem trait in lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 826. doi:10.1158/1538-7445.AM2017-826