title: Upregulation of NRF2 through autophagy/ERK 1/2 ameliorates ionizing radiation induced cell death of human osteosarcoma U-2 OS.
abstract: The antioxidative response mediated by transcription factor NRF2 is thought to be a pivotal cellular defense system against various extrinsic stresses. It has been reported that activation of the NRF2 pathway confers cells with resistance to ionizing radiation-induced damage. However, the underlying mechanism remains largely unknown. In the current research, it was found that α-particle radiation has the ability to stimulate NRF2 expression in human osteosarcoma U-2 OS cells. Knockdown of cellular NRF2 level by shRNA-mediated gene silencing decreased the survival rate, increased the micronucleus formation rate and apoptosis rate in irradiated cells. Consistently, knockdown of NRF2 resulted in decreased expression of p65 and Bcl-2, and increased expression of p53 and Bax. Besides, it was observed that increased expression of NRF2 was partially dependent on radiation induced phosphorylation of ERK 1/2. Further results showed that radiation promoted autophagy flux which leads to the enhanced phosphorylation of ERK 1/2, as evidenced by the resultls that knockdown of ATG5 (Autophagy protein 5) gene by shRNA suppressed both radiation induced ERK 1/2 phosphorylation and NRF2 upregulation. Based on these results, it is proposed that attenuation of NRF2 antioxidative pathway can sensitize U-2 OS cells to radiation, where NRF2 antioxidative response is regulated by autophagy mediated activation of ERK 1/2 kinases.
authors.affiliation: School of Nuclear Science and Technology, University of Science and Technology of China, Hefei, 230027, PR China; Key Laboratory of Ion Beam Bioengineering, Hefei Institute of Physical Science, Chinese Academy of Sciences and Anhui Province, No. 350 of Shushanhu Road, Hefei, 230031, PR China.
authors.forename: Ni
authors.initials: N
authors.lastname: Chen
authors.affiliation: Key Laboratory of Ion Beam Bioengineering, Hefei Institute of Physical Science, Chinese Academy of Sciences and Anhui Province, No. 350 of Shushanhu Road, Hefei, 230031, PR China.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.affiliation: International Open Laboratory of National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Teruaki
authors.initials: T
authors.lastname: Konishi
authors.affiliation: Key Laboratory of Ion Beam Bioengineering, Hefei Institute of Physical Science, Chinese Academy of Sciences and Anhui Province, No. 350 of Shushanhu Road, Hefei, 230031, PR China. Electronic address: wangjun0457@ipp.ac.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
mesh_terms: D017209:Apoptosis / Q000528:radiation effects; D001343:Autophagy; D016923:Cell Death / Q000528:radiation effects*; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D006801:Humans; D020935:MAP Kinase Signaling System; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D011839:Radiation, Ionizing; D015854:Up-Regulation
chemical_list: D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human
keywords: Autophagy; ERK1/2; Ionizing radiation; NRF2; Radio-sensitization