4.7 Article

Nrf2 inhibition sensitizes breast cancer stem cells to ionizing radiation via suppressing DNA repair

Journal

FREE RADICAL BIOLOGY AND MEDICINE
Volume 169, Issue -, Pages 238-247

Publisher

ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2021.04.006

Keywords

Nrf2; Breast cancer stem cells; Ionizing radiation; Reactive oxygen species; DNA repair; DNA-PK

Funding

  1. NIH [P20GM103542, U54CA210962]
  2. National Natural Science Foundation of China [81700012]

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The study reveals that radiation can activate Nrf2 signaling, which counteracts the killing effect of radiation on cancer stem cells. Inhibiting the activation of Nrf2 can enhance the killing effect of radiation on therapy-resistant cancer stem cells.
Radiation is widely used for cancer treatment but the radioresistance properties of cancer stem cells (CSCs) pose a significant challenge to the success of cancer therapy. Nuclear factor erythroid-2-related factor 2 (Nrf2) has emerged as a prominent regulator of cellular antioxidant responses and its over-activation is associated with drug resistant in cancer cells. However, the role of Nrf2 signaling in regulating the response of CSCs to irradiation has yet to be defined. Here, we show that exposure of triple-negative breast cancer (TNBC) cells to ionizing radiation (IR) upregulates Nrf2 expression and promotes its nuclear translocation in a reactive oxygen species (ROS)dependent manner. Ectopic overexpression of Nrf2 attenuates, whereas knockdown of Nrf2 potentiates IRinduced killing of TNBC CSCs. Mechanistically, we found that Nrf2 knockdown increases IR-induced ROS production and impedes DNA repair at least in part via inhibition of DNA-PK. Furthermore, activation of Nrf2 by sulforaphane diminishes, whereas inhibition of Nrf2 by ML385 enhances IR-induced killing of TNBC CSCs. Collectively, these results demonstrate that IR-induced ROS production can activate Nrf2 signaling, which in turn counteracts the killing effect of irradiation. Therefore, pharmacological inhibition of IR-induced Nrf2 activation by ML385 could be a new therapeutic approach to sensitize therapy-resistant CSCs to radiotherapy.

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