KEAP1 is a redox sensitive target that arbitrates the opposing radiosensitive effects of parthenolide in normal and cancer cells. Xu, Y., Fang, F., Miriyala, S., Crooks, P. A, Oberley, T. D, Chaiswing, L., Noel, T., Holley, A. K, Zhao, Y., Kiningham, K. K, Clair, D. K S., & Clair, W. H S. Cancer research, 73(14):4406--4417, July, 2013. doi abstract bibtex 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.
@article{xu_keap1_2013,
title = {{KEAP}1 is a redox sensitive target that arbitrates the opposing radiosensitive effects of parthenolide in normal and cancer cells},
volume = {73},
issn = {1538-7445},
doi = {10.1158/0008-5472.CAN-12-4297},
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.},
number = {14},
journal = {Cancer research},
author = {Xu, Yong and Fang, Fang and Miriyala, Sumitra and Crooks, Peter A and Oberley, Terry D and Chaiswing, Luksana and Noel, Teresa and Holley, Aaron K and Zhao, Yanming and Kiningham, Kelley K and Clair, Daret K St and Clair, William H St},
month = jul,
year = {2013},
pmid = {23674500},
keywords = {Animals, Antioxidants, Carrier Proteins, Cell Line, Cell Line, Tumor, Epithelial Cells, Humans, Intracellular Signaling Peptides and Proteins, Kelch-Like ECH-Associated Protein 1, Male, Mice, Mice, Nude, Mitochondrial Proteins, NF-E2-Related Factor 2, Oxidation-Reduction, Oxidative Stress, Phosphoprotein Phosphatases, Prostatic Neoplasms, Radiation Tolerance, Radiation-Sensitizing Agents, Random Allocation, Reactive Oxygen Species, Sesquiterpenes, Thioredoxins, Ubiquitin, Xenograft Model Antitumor Assays, bcl-X Protein},
pages = {4406--4417}
}
Downloads: 0
{"_id":"AA8sdS5rXq5q9izGt","bibbaseid":"xu-fang-miriyala-crooks-oberley-chaiswing-noel-holley-etal-keap1isaredoxsensitivetargetthatarbitratestheopposingradiosensitiveeffectsofparthenolideinnormalandcancercells-2013","downloads":0,"creationDate":"2017-11-16T03:38:51.667Z","title":"KEAP1 is a redox sensitive target that arbitrates the opposing radiosensitive effects of parthenolide in normal and cancer cells","author_short":["Xu, Y.","Fang, F.","Miriyala, S.","Crooks, P. A","Oberley, T. D","Chaiswing, L.","Noel, T.","Holley, A. K","Zhao, Y.","Kiningham, K. K","Clair, D. K S.","Clair, W. H S."],"year":2013,"bibtype":"article","biburl":"https://api.zotero.org/users/585595/collections/74C3SXBK/items?key=1nXMl6HeUfXzWafuqAa4Ryj2&format=bibtex&limit=100\"></iframe","bibdata":{"bibtype":"article","type":"article","title":"KEAP1 is a redox sensitive target that arbitrates the opposing radiosensitive effects of parthenolide in normal and cancer cells","volume":"73","issn":"1538-7445","doi":"10.1158/0008-5472.CAN-12-4297","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.","number":"14","journal":"Cancer research","author":[{"propositions":[],"lastnames":["Xu"],"firstnames":["Yong"],"suffixes":[]},{"propositions":[],"lastnames":["Fang"],"firstnames":["Fang"],"suffixes":[]},{"propositions":[],"lastnames":["Miriyala"],"firstnames":["Sumitra"],"suffixes":[]},{"propositions":[],"lastnames":["Crooks"],"firstnames":["Peter","A"],"suffixes":[]},{"propositions":[],"lastnames":["Oberley"],"firstnames":["Terry","D"],"suffixes":[]},{"propositions":[],"lastnames":["Chaiswing"],"firstnames":["Luksana"],"suffixes":[]},{"propositions":[],"lastnames":["Noel"],"firstnames":["Teresa"],"suffixes":[]},{"propositions":[],"lastnames":["Holley"],"firstnames":["Aaron","K"],"suffixes":[]},{"propositions":[],"lastnames":["Zhao"],"firstnames":["Yanming"],"suffixes":[]},{"propositions":[],"lastnames":["Kiningham"],"firstnames":["Kelley","K"],"suffixes":[]},{"propositions":[],"lastnames":["Clair"],"firstnames":["Daret","K","St"],"suffixes":[]},{"propositions":[],"lastnames":["Clair"],"firstnames":["William","H","St"],"suffixes":[]}],"month":"July","year":"2013","pmid":"23674500","keywords":"Animals, Antioxidants, Carrier Proteins, Cell Line, Cell Line, Tumor, Epithelial Cells, Humans, Intracellular Signaling Peptides and Proteins, Kelch-Like ECH-Associated Protein 1, Male, Mice, Mice, Nude, Mitochondrial Proteins, NF-E2-Related Factor 2, Oxidation-Reduction, Oxidative Stress, Phosphoprotein Phosphatases, Prostatic Neoplasms, Radiation Tolerance, Radiation-Sensitizing Agents, Random Allocation, Reactive Oxygen Species, Sesquiterpenes, Thioredoxins, Ubiquitin, Xenograft Model Antitumor Assays, bcl-X Protein","pages":"4406--4417","bibtex":"@article{xu_keap1_2013,\n\ttitle = {{KEAP}1 is a redox sensitive target that arbitrates the opposing radiosensitive effects of parthenolide in normal and cancer cells},\n\tvolume = {73},\n\tissn = {1538-7445},\n\tdoi = {10.1158/0008-5472.CAN-12-4297},\n\tabstract = {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.},\n\tnumber = {14},\n\tjournal = {Cancer research},\n\tauthor = {Xu, Yong and Fang, Fang and Miriyala, Sumitra and Crooks, Peter A and Oberley, Terry D and Chaiswing, Luksana and Noel, Teresa and Holley, Aaron K and Zhao, Yanming and Kiningham, Kelley K and Clair, Daret K St and Clair, William H St},\n\tmonth = jul,\n\tyear = {2013},\n\tpmid = {23674500},\n\tkeywords = {Animals, Antioxidants, Carrier Proteins, Cell Line, Cell Line, Tumor, Epithelial Cells, Humans, Intracellular Signaling Peptides and Proteins, Kelch-Like ECH-Associated Protein 1, Male, Mice, Mice, Nude, Mitochondrial Proteins, NF-E2-Related Factor 2, Oxidation-Reduction, Oxidative Stress, Phosphoprotein Phosphatases, Prostatic Neoplasms, Radiation Tolerance, Radiation-Sensitizing Agents, Random Allocation, Reactive Oxygen Species, Sesquiterpenes, Thioredoxins, Ubiquitin, Xenograft Model Antitumor Assays, bcl-X Protein},\n\tpages = {4406--4417}\n}\n\n","author_short":["Xu, Y.","Fang, F.","Miriyala, S.","Crooks, P. A","Oberley, T. D","Chaiswing, L.","Noel, T.","Holley, A. K","Zhao, Y.","Kiningham, K. K","Clair, D. K S.","Clair, W. H S."],"key":"xu_keap1_2013","id":"xu_keap1_2013","bibbaseid":"xu-fang-miriyala-crooks-oberley-chaiswing-noel-holley-etal-keap1isaredoxsensitivetargetthatarbitratestheopposingradiosensitiveeffectsofparthenolideinnormalandcancercells-2013","role":"author","urls":{},"keyword":["Animals","Antioxidants","Carrier Proteins","Cell Line","Cell Line","Tumor","Epithelial Cells","Humans","Intracellular Signaling Peptides and Proteins","Kelch-Like ECH-Associated Protein 1","Male","Mice","Mice","Nude","Mitochondrial Proteins","NF-E2-Related Factor 2","Oxidation-Reduction","Oxidative Stress","Phosphoprotein Phosphatases","Prostatic Neoplasms","Radiation Tolerance","Radiation-Sensitizing Agents","Random Allocation","Reactive Oxygen Species","Sesquiterpenes","Thioredoxins","Ubiquitin","Xenograft Model Antitumor Assays","bcl-X Protein"],"downloads":0},"search_terms":["keap1","redox","sensitive","target","arbitrates","opposing","radiosensitive","effects","parthenolide","normal","cancer","cells","xu","fang","miriyala","crooks","oberley","chaiswing","noel","holley","zhao","kiningham","clair","clair"],"keywords":["animals","antioxidants","carrier proteins","cell line","cell line","tumor","epithelial cells","humans","intracellular signaling peptides and proteins","kelch-like ech-associated protein 1","male","mice","mice","nude","mitochondrial proteins","nf-e2-related factor 2","oxidation-reduction","oxidative stress","phosphoprotein phosphatases","prostatic neoplasms","radiation tolerance","radiation-sensitizing agents","random allocation","reactive oxygen species","sesquiterpenes","thioredoxins","ubiquitin","xenograft model antitumor assays","bcl-x protein"],"authorIDs":[],"dataSources":["Eax3HqcG6fcDtsCq9"]}