title: KEAP1 is a redox sensitive target that arbitrates the opposing radiosensitive effects of parthenolide in normal and cancer cells.
abstract: Elevated oxidative stress is observed more frequently in cancer cells than in normal cells. It is therefore expected that additional exposure to a low level of reactive oxygen species (ROS) will push cancer cells toward death, whereas normal cells might maintain redox homeostasis through adaptive antioxidant responses. We previously showed that parthenolide enhances ROS production in prostate cancer cells through activation of NADPH oxidase. The present study identifies KEAP1 as the downstream redox target that contributes to parthenolide's radiosensitization effect in prostate cancer cells. In vivo, parthenolide increases radiosensitivity of mouse xenograft tumors but protects normal prostate and bladder tissues against radiation-induced injury. Mechanistically, parthenolide increases the level of cellular ROS and causes oxidation of thioredoxin (TrX) in prostate cancer cells, leading to a TrX-dependent increase in a reduced state of KEAP1, which in turn leads to KEAP1-mediated PGAM5 and Bcl-xL (BCL2L1) degradation. In contrast, parthenolide increases oxidation of KEAP1 in normal prostate epithelial cells, leading to increased Nrf2 (NFE2L2) levels and subsequent Nrf2-dependent expression of antioxidant enzymes. These results reveal a novel redox-mediated modification of KEAP1 in controlling the differential effect of parthenolide on tumor and normal cell radiosensitivity. Furthermore, they show it is possible to develop a tumor-specific radiosensitizing agent with radioprotective properties in normal cells.
authors.affiliation: Graduate Center for Toxicology, Department of Radiation Medicine, University of Kentucky, Lexington, Kentucky 40536, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.forename: Fang
authors.initials: F
authors.lastname: Fang
authors.forename: Sumitra
authors.initials: S
authors.lastname: Miriyala
authors.forename: Peter A
authors.initials: PA
authors.lastname: Crooks
authors.forename: Terry D
authors.initials: TD
authors.lastname: Oberley
authors.forename: Luksana
authors.initials: L
authors.lastname: Chaiswing
authors.forename: Teresa
authors.initials: T
authors.lastname: Noel
authors.forename: Aaron K
authors.initials: AK
authors.lastname: Holley
authors.forename: Yanming
authors.initials: Y
authors.lastname: Zhao
authors.forename: Kelley K
authors.initials: KK
authors.lastname: Kiningham
authors.forename: Daret K St
authors.initials: DK
authors.lastname: Clair
authors.forename: William H St
authors.initials: WH
authors.lastname: Clair
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1; D008297:Male; D051379:Mice; D008819:Mice, Nude; D024101:Mitochondrial Proteins / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D010749:Phosphoprotein Phosphatases; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000532:radiotherapy; D011836:Radiation Tolerance; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D011897:Random Allocation; D017382:Reactive Oxygen Species / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology*; D013879:Thioredoxins / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D000975:Antioxidants; C494811:BCL2L1 protein, human; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D024101:Mitochondrial Proteins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D011838:Radiation-Sensitizing Agents; D017382:Reactive Oxygen Species; D012717:Sesquiterpenes; D025801:Ubiquitin; D051020:bcl-X Protein; C002669:parthenolide; D013879:Thioredoxins; C529563:PGAM5 protein, human; D010749:Phosphoprotein Phosphatases