title: APE1 promotes antioxidant capacity by regulating Nrf-2 function through a redox-dependent mechanism.
abstract: APE1 is a multifunctional protein that has recently been implicated in protecting cells from oxidative stress. In the current study, we confirmed that APE1׳s effect on cellular antioxidant capacity is related to its redox activity through the use of an APE1 functional mutant, and we investigated the mechanism through which this multifunctional protein affects the function of the transcription factor Nrf-2 in regulating oxidative stress-induced genes. Using a pair of mutants for both the redox activity and the acetylation-regulated activity of APE1, in vitro assays showed that the redox activity of APE1 is crucial for its nuclear association with Nrf-2 and subsequent activation of Nrf-2׳s transcription of several downstream genes during oxidative challenge. Important oxidative stress genes are affected by APE1 redox activity, including Hmox1, Gstm1, and Txnrd1. In addition, utilizing human non-small-cell lung cancer sample tissue as well as a nude mouse xenograft model, we determined that APE1 expression levels are inversely correlated to oxidative stress in vivo. These findings indicated that interference with these crucial functions of APE1 shows promise in preventing resistance to certain radiotherapies and that further research is necessary to understand APE1׳s complex roles in regulating both the basal redox status and the oxidative stress state of the cellular environment.
authors.affiliation: Cancer Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, People׳s Republic of China.
authors.forename: Jin-Lu
authors.initials: JL
authors.lastname: Shan
authors.affiliation: Department of Oral and Maxillofacial Surgery, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, People׳s Republic of China.
authors.forename: Hai-Tao
authors.initials: HT
authors.lastname: He
authors.affiliation: Cancer Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, People׳s Republic of China.
authors.forename: Meng-Xia
authors.initials: MX
authors.lastname: Li
authors.affiliation: Cancer Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, People׳s Republic of China.
authors.forename: Jian-Wu
authors.initials: JW
authors.lastname: Zhu
authors.affiliation: Cancer Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, People׳s Republic of China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Cancer Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, People׳s Republic of China.
authors.forename: Nan
authors.initials: N
authors.lastname: Hu
authors.affiliation: Cancer Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, People׳s Republic of China.
authors.forename: Ge
authors.initials: G
authors.lastname: Wang
authors.affiliation: Cancer Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, People׳s Republic of China.
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
authors.affiliation: Cancer Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, People׳s Republic of China.
authors.forename: Xue-Qin
authors.initials: XQ
authors.lastname: Yang
authors.affiliation: Department of Respiration, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, People׳s Republic of China.
authors.forename: Yong
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Pathology, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, People׳s Republic of China.
authors.forename: Hua-Liang
authors.initials: HL
authors.lastname: Xiao
authors.affiliation: Department of General surgery, Research Institute of Surgery, Southwest Hospital, Third Military Medical University, Chongqing 400042, People׳s Republic of China.
authors.forename: Wei-Dong
authors.initials: WD
authors.lastname: Tong
authors.affiliation: Cancer Center, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing 400042, People׳s Republic of China. Electronic address: yangzhenzhou@sohu.com.
authors.forename: Zhen-Zhou
authors.initials: ZZ
authors.lastname: Yang
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D009367:Neoplasm Staging; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase
keywords: APE1; Antioxidant capacity; Nrf-2; Redox