title: Downregulation of Nrf2 promotes radiation-induced apoptosis through Nrf2 mediated Notch signaling in non-small cell lung cancer cells.
abstract: The nuclear factor erythroid-2-related factor 2 (Nrf2) is a crucial regulator of the cellular antioxidant system. Nrf2 is often constitutively activated in non-small cell lung cancer (NSCLC) cell lines, which promotes cytoprotection against oxidative stress and xenobiotics. Notch1 signaling is critically implicated in cell fate determination. It has been reported that Nf2 strongly regulates Notch1 activity. However, the role of Nrf2 mediated Notch1 signaling in response to ionizing radiation (IR) remains elusive. We report that knockdown of Nrf2 promotes radiation-induced apoptosis through Nrf2 mediated Notch1 signaling in NSCLC cells. IR activated Nrf2 in a dose-dependent manner and the expression of Nrf2 was significantly elevated at 4 h after exposure. RNAi-mediated reduction of Nrf2 significantly increased endogenous ROS levels, and decreased the expression of glutamate cysteine ligase catalytic subunit (GCLC), heme oxygenase-1 (HO-1) and NAD (P) H quinine oxidoreductase-1 (NQO1) in irradiated cells. Furthermore, decrease in Nrf2 expression significantly dampened Notch1 expression following ionizing radiation exposure, and potentiated IR-induced cellular apoptosis. These results demonstrated that Nrf2 could be activated by ionizing radiation, knockdown of Nrf2 could promote radiation induced apoptosis and Nrf2-mediated Notch signaling is an important determinant in radioresistance of lung cancer cells.
authors.affiliation: Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, Gansu 730000, P.R. China.
authors.forename: Qiuyue
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, Gansu 730000, P.R. China.
authors.forename: Aihong
authors.initials: A
authors.lastname: Mao
authors.affiliation: Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, Gansu 730000, P.R. China.
authors.forename: Jiawei
authors.initials: J
authors.lastname: Yan
authors.affiliation: Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, Gansu 730000, P.R. China.
authors.forename: Chao
authors.initials: C
authors.lastname: Sun
authors.affiliation: Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, Gansu 730000, P.R. China.
authors.forename: Cuixia
authors.initials: C
authors.lastname: Di
authors.affiliation: Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, Gansu 730000, P.R. China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, Gansu 730000, P.R. China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Li
authors.affiliation: South China Agricultural University, Guangzhou, Guangdong 510642, P.R. China.
authors.forename: Ruoshui
authors.initials: R
authors.lastname: Guo
authors.affiliation: Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, Gansu 730000, P.R. China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D045744:Cell Line, Tumor; D019610:Cytoprotection / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics*; D005721:Glutamate-Cysteine Ligase / Q000235:genetics; D051547:Heme Oxygenase-1 / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D018384:Oxidative Stress / Q000235:genetics; D034622:RNA Interference / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D017382:Reactive Oxygen Species; D051880:Receptors, Notch; D051547:Heme Oxygenase-1; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C000609392:GCLC protein, human; D005721:Glutamate-Cysteine Ligase