title: RelB Expression Determines the Differential Effects of Ascorbic Acid in Normal and Cancer Cells.
abstract: Cancer cells typically experience higher oxidative stress than normal cells, such that elevating pro-oxidant levels can trigger cancer cell death. Although pre-exposure to mild oxidative agents will sensitize cancer cells to radiation, this pre-exposure may also activate the adaptive stress defense system in normal cells. Ascorbic acid is a prototype redox modulator that when infused intravenously appears to kill cancers without injury to normal tissues; however, the mechanisms involved remain elusive. In this study, we show how ascorbic acid kills cancer cells and sensitizes prostate cancer to radiation therapy while also conferring protection upon normal prostate epithelial cells against radiation-induced injury. We found that the NF-κB transcription factor RelB is a pivotal determinant in the differential radiosensitization effects of ascorbic acid in prostate cancer cells and normal prostate epithelial cells. Mechanistically, high reactive oxygen species concentrations suppress RelB in cancer cells. RelB suppression decreases expression of the sirtuin SIRT3 and the powerful antioxidant MnSOD, which in turn increases oxidative and metabolic stresses in prostate cancer cells. In contrast, ascorbic acid enhances RelB expression in normal cells, improving antioxidant and metabolic defenses against radiation injury. In addition to showing how RelB mediates the differential effects of ascorbic acid on cancer and normal tissue radiosensitivities, our work also provides a proof of concept for the existence of redox modulators that can improve the efficacy of radiotherapy while protecting against normal tissue injury in cancer settings.Cancer Res; 77(6); 1345-56. ©2017 AACR.
authors.affiliation: Department of Toxicology and Cancer Biology, Markey Cancer Center, University of Kentucky, Lexington, Kentucky.|Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Wei
authors.affiliation: Department of Toxicology and Cancer Biology, Markey Cancer Center, University of Kentucky, Lexington, Kentucky.|Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Radiation Medicine, Markey Cancer Center, University of Kentucky, Lexington, Kentucky.
authors.forename: Fang Fang
authors.initials: FF
authors.lastname: Xu
authors.affiliation: Department of Toxicology and Cancer Biology, Markey Cancer Center, University of Kentucky, Lexington, Kentucky.
authors.forename: Luksana
authors.initials: L
authors.lastname: Chaiswing
authors.affiliation: Department of Toxicology and Cancer Biology, Markey Cancer Center, University of Kentucky, Lexington, Kentucky.
authors.forename: David
authors.initials: D
authors.lastname: Schnell
authors.affiliation: Department of Toxicology and Cancer Biology, Markey Cancer Center, University of Kentucky, Lexington, Kentucky.
authors.forename: Teresa
authors.initials: T
authors.lastname: Noel
authors.affiliation: Biostatistics Core, Markey Cancer Center, University of Kentucky, Lexington, Kentucky.
authors.forename: Chi
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China. dstcl00@uky.edu stclair@uky.edu jinfeichen@sohu.com.
authors.forename: Jinfei
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Toxicology and Cancer Biology, Markey Cancer Center, University of Kentucky, Lexington, Kentucky. dstcl00@uky.edu stclair@uky.edu jinfeichen@sohu.com.
authors.forename: Daret K
authors.initials: DK
authors.lastname: St Clair
authors.affiliation: Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China. dstcl00@uky.edu stclair@uky.edu jinfeichen@sohu.com.
authors.forename: William H
authors.initials: WH
authors.lastname: St Clair
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001205:Ascorbic Acid / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D018384:Oxidative Stress / Q000187:drug effects* / Q000528:radiation effects; D011467:Prostate / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011836:Radiation Tolerance / Q000187:drug effects; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D051841:Transcription Factor RelB / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000975:Antioxidants; C497593:RELB protein, human; D011838:Radiation-Sensitizing Agents; D017382:Reactive Oxygen Species; D051841:Transcription Factor RelB; D013482:Superoxide Dismutase; D001205:Ascorbic Acid