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Article ; Online: Nucleophosmin Plays a Role in Repairing DNA Damage and Is a Target for Cancer Treatment.

Sekhar, Konjeti R / Freeman, Michael L

2023 Volume 83, Issue 10, Page(s) 1573–1580

Abstract: Nucleophosmin (NPM1) is frequently mutated in acute myeloid leukemia, and NPM1 expression is elevated in several cancer types. NPM1 is a multifunctional oligomeric protein involved in numerous cellular functions that include participating in liquid- ... ...

Abstract	Nucleophosmin (NPM1) is frequently mutated in acute myeloid leukemia, and NPM1 expression is elevated in several cancer types. NPM1 is a multifunctional oligomeric protein involved in numerous cellular functions that include participating in liquid-liquid phase separation, ribosome biogenesis, chaperoning of histones, and modulation of transcription. In this review, we discuss the underappreciated role of NPM1 in DNA damage repair, specifically Polη-mediated translesion synthesis, base excision, and homologous recombination and highlight the therapeutic potential of NPM1 targeting in cancer treatment.
MeSH term(s)	Humans ; Nucleophosmin ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Mutation ; DNA Damage ; DNA Repair ; Leukemia, Myeloid, Acute/therapy ; Leukemia, Myeloid, Acute/drug therapy
Chemical Substances	Nucleophosmin (117896-08-9) ; Nuclear Proteins
Language	English
Publishing date	2023-03-06
Publishing country	United States
Document type	Review ; Journal Article
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-22-3631
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Article ; Online: Ferroptosis Inducers in Thyroid Cancer.

Sekhar, Konjeti R / Cyr, Sriram / Baregamian, Naira

World journal of surgery

2022 Volume 47, Issue 2, Page(s) 371–381

Abstract: Purpose: Papillary thyroid carcinoma (PTC) progression imparts reduced patient survival. Tumor resistance and progression can be influenced by Glutathione (GSH) metabolism. Glutathione peroxidase 4 (GPX4) regulates GSH oxidation to prevent lipid ... ...

Abstract	Purpose: Papillary thyroid carcinoma (PTC) progression imparts reduced patient survival. Tumor resistance and progression can be influenced by Glutathione (GSH) metabolism. Glutathione peroxidase 4 (GPX4) regulates GSH oxidation to prevent lipid peroxidation of cell membranes during increased oxidative stress and regulates ferroptosis cell death pathway in tumor cells. This study examines the differential ferroptosis effects by GPX4 inhibitors in thyroid cancer cell and 3-D spheroid in vitro models. Materials and methods: We examined differential effects of GPX4 inhibitors on PTC cells (K1, MDA-T32, MDA-T68) with BRAF and RAS mutations, and TERT promoter and PIK3CA co-mutations. The effects of GPX4 inhibitors on ferroptosis activation, proliferation, oxidative stress, and activation of signaling pathways were assessed by Western blot, total (GSH) and oxidized glutathione (GSSG) levels, ROS induction, RT-qPCR, migration, and proliferation assays. Results: GPX4 inhibitors induced ferroptosis, rising ROS, GSH depletion, arrested tumor cell migration, increased DNA damage, suppressed mTOR pathway and DNA repair response in PTC cells in vitro. Differential responses to DNA damage and GPX4 levels were observed between 3-D PTC spheroids and thyroid cancer cells in a monolayer model. Conclusion: Effective GPX4 inhibition with various inhibitors induced a robust but differential activation of ferroptosis in monolayer thyroid tumor cell and 3-D PTC spheroid models. Our study is the first of its kind to determine the differential effects of GPX4 inhibitors on thyroid cancer cells with diverse mutational signatures. We have identified a novel mechanism of action of GPX4 inhibition in preclinical in vitro models of thyroid cancer that can be further exploited for therapeutic benefit in advanced therapy-resistant thyroid cancers.
MeSH term(s)	Humans ; Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism ; Glutathione Peroxidase/genetics ; Glutathione Peroxidase/metabolism ; Ferroptosis ; Reactive Oxygen Species/metabolism ; Thyroid Neoplasms/drug therapy ; Thyroid Neoplasms/genetics
Chemical Substances	Phospholipid Hydroperoxide Glutathione Peroxidase (EC 1.11.1.12) ; Glutathione Peroxidase (EC 1.11.1.9) ; Reactive Oxygen Species
Language	English
Publishing date	2022-10-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	224043-9
ISSN	1432-2323 ; 0364-2313
ISSN (online)	1432-2323
ISSN	0364-2313
DOI	10.1007/s00268-022-06738-z
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Article ; Online: Glutathione peroxidase 4 inhibition induces ferroptosis and mTOR pathway suppression in thyroid cancer.

Sekhar, Konjeti R / Hanna, David N / Cyr, Sriram / Baechle, Jordan J / Kuravi, Sudhakiranmayi / Balusu, Ramesh / Rathmell, Kimryn / Baregamian, Naira

Scientific reports

2022 Volume 12, Issue 1, Page(s) 19396

Abstract: Papillary thyroid carcinoma (PTC) demonstrates significantly reduced patient survival with metastatic progression. Tumor progression can be influenced by metabolism, including antioxidant glutathione (GSH). Glutathione peroxidase 4 (GPX4) is a ... ...

Abstract	Papillary thyroid carcinoma (PTC) demonstrates significantly reduced patient survival with metastatic progression. Tumor progression can be influenced by metabolism, including antioxidant glutathione (GSH). Glutathione peroxidase 4 (GPX4) is a selenoenzyme that uses GSH as a co-factor to regulate lipid peroxidation of cell membranes during increased oxidative stress. GPX4 suppression in tumor cells can induce ferroptosis. This study aims to examine ferroptosis as a potentially critical pathway in effective targeting of thyroid cancer (TC) cells. We treated human TC cells (K1, MDA-T68, MDA-T32, TPC1) with (1S,3R)-RSL3 (RSL3), a small-molecule inhibitor of GPX4 and examined the effects on ferroptosis, tumor cell survival and migration, spheroid formation, oxidative stress, DNA damage repair response, and mTOR signaling pathway in vitro. GPX4 inhibition activated ferroptosis, inducing TC cell death, rapid rise in reactive oxygen species and effectively arrested cell migration in vitro. Suppression of mTOR signaling pathway triggered autophagy. GPX4 genetic knockdown mirrored RSL3 effect on mTOR pathway suppression. RSL3 subdued DNA damage repair response by suppressing phosphorylation of nucleophosmin 1 (NPM1). Thus, observed potent induction of ferroptosis, GPX4-dependent novel suppression of mTOR pathway and DNA damage repair response in preclinical in vitro model of TC supports GPX4 targeting for therapeutic benefit in advanced therapy-resistant thyroid cancers.
MeSH term(s)	Humans ; Ferroptosis ; Phospholipid Hydroperoxide Glutathione Peroxidase ; Cell Death ; Glutathione Peroxidase/metabolism ; Glutathione/metabolism ; Thyroid Neoplasms/drug therapy ; TOR Serine-Threonine Kinases
Chemical Substances	Phospholipid Hydroperoxide Glutathione Peroxidase (EC 1.11.1.12) ; Glutathione Peroxidase (EC 1.11.1.9) ; Glutathione (GAN16C9B8O) ; TOR Serine-Threonine Kinases (EC 2.7.11.1) ; MTOR protein, human (EC 2.7.1.1)
Language	English
Publishing date	2022-11-12
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-022-23906-2
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Article ; Online: Glutathione peroxidase 4 inhibition induces ferroptosis and mTOR pathway suppression in thyroid cancer

Konjeti R. Sekhar / David N. Hanna / Sriram Cyr / Jordan J. Baechle / Sudhakiranmayi Kuravi / Ramesh Balusu / Kimryn Rathmell / Naira Baregamian

Scientific Reports, Vol 12, Iss 1, Pp 1-

2022 Volume 10

Abstract: Abstract Papillary thyroid carcinoma (PTC) demonstrates significantly reduced patient survival with metastatic progression. Tumor progression can be influenced by metabolism, including antioxidant glutathione (GSH). Glutathione peroxidase 4 (GPX4) is a ... ...

Abstract	Abstract Papillary thyroid carcinoma (PTC) demonstrates significantly reduced patient survival with metastatic progression. Tumor progression can be influenced by metabolism, including antioxidant glutathione (GSH). Glutathione peroxidase 4 (GPX4) is a selenoenzyme that uses GSH as a co-factor to regulate lipid peroxidation of cell membranes during increased oxidative stress. GPX4 suppression in tumor cells can induce ferroptosis. This study aims to examine ferroptosis as a potentially critical pathway in effective targeting of thyroid cancer (TC) cells. We treated human TC cells (K1, MDA-T68, MDA-T32, TPC1) with (1S,3R)-RSL3 (RSL3), a small-molecule inhibitor of GPX4 and examined the effects on ferroptosis, tumor cell survival and migration, spheroid formation, oxidative stress, DNA damage repair response, and mTOR signaling pathway in vitro. GPX4 inhibition activated ferroptosis, inducing TC cell death, rapid rise in reactive oxygen species and effectively arrested cell migration in vitro. Suppression of mTOR signaling pathway triggered autophagy. GPX4 genetic knockdown mirrored RSL3 effect on mTOR pathway suppression. RSL3 subdued DNA damage repair response by suppressing phosphorylation of nucleophosmin 1 (NPM1). Thus, observed potent induction of ferroptosis, GPX4-dependent novel suppression of mTOR pathway and DNA damage repair response in preclinical in vitro model of TC supports GPX4 targeting for therapeutic benefit in advanced therapy-resistant thyroid cancers.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2022-11-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
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Article: Metabolism of parathyroid organoids.

Sekhar, Konjeti R / Codreanu, Simona G / Williams, Olivia C / Rathmell, Jeffrey C / Rathmell, W Kimryn / McLean, John A / Sherrod, Stacy D / Baregamian, Naira

Frontiers in endocrinology

2023 Volume 14, Page(s) 1223312

Abstract: Introduction: We successfully developed a broad spectrum of patient-derived endocrine organoids (PDO) from benign and malignant neoplasms of thyroid, parathyroid, and adrenal glands. In this study, we employed functionally intact parathyroid PDOs from ... ...

Abstract	Introduction: We successfully developed a broad spectrum of patient-derived endocrine organoids (PDO) from benign and malignant neoplasms of thyroid, parathyroid, and adrenal glands. In this study, we employed functionally intact parathyroid PDOs from benign parathyroid tissues to study primary hyperparathyroidism (PHPT), a common endocrine metabolic disease. As proof of concept, we examined the utility of parathyroid PDOs for bioenergetic and metabolic screening and assessed whether parathyroid PDO metabolism recapitulated matched PHPT tissues. Methods: Our study methods included a fine-needle aspiration (FNA)-based technique to establish parathyroid PDOs from human PHPT tissues (n=6) in semi-solid culture conditions for organoid formation, growth, and proliferation. Mass spectrometry metabolomic analysis of PHPT tissues and patient-matched PDOs, and live cell bioenergetic profiling of parathyroid PDOs with extracellular flux analyses, were performed. Functional analysis cryopreserved and re-cultured parathyroid PDOs for parathyroid hormone (PTH) secretion was performed using ELISA hormone assays. Results and discussion: Our findings support both the feasibility of parathyroid PDOs for metabolic and bioenergetic profiling and reinforce metabolic recapitulation of PHPT tissues by patient-matched parathyroid PDOs. Cryopreserved parathyroid PDOs exhibited preserved, rapid, and sustained secretory function after thawing. In conclusion, successful utilization of parathyroid PDOs for metabolic profiling further affirms the feasibility of promising endocrine organoid platforms for future metabolic studies and broader multiplatform and translational applications for therapeutic advancements of parathyroid and other endocrine applications.
MeSH term(s)	Humans ; Parathyroid Glands/metabolism ; Biopsy, Fine-Needle/methods ; Thyroid Gland ; Organoids
Language	English
Publishing date	2023-07-10
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2592084-4
ISSN	1664-2392
ISSN	1664-2392
DOI	10.3389/fendo.2023.1223312
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Article ; Online: Nrf2 promotes survival following exposure to ionizing radiation.

Sekhar, Konjeti R / Freeman, Michael L

Free radical biology & medicine

2015 Volume 88, Issue Pt B, Page(s) 268–274

Abstract: Nrf2 is a transcription factor that promotes antioxidant and drug-metabolizing gene expression. It also regulates the transcription of genes involved in carbohydrate and lipid metabolism, NADPH regeneration, and heme and iron metabolism, as well as ... ...

Abstract	Nrf2 is a transcription factor that promotes antioxidant and drug-metabolizing gene expression. It also regulates the transcription of genes involved in carbohydrate and lipid metabolism, NADPH regeneration, and heme and iron metabolism, as well as proteasome metabolism. Emerging research has identified Nrf2 as a critical factor for promoting survival of mammalian cells subjected to ionizing radiation. At a mechanistic level, Nrf2 promotes the repair of DNA damage and drives detoxification of superoxide that is generated hours to days after irradiation. This review summarizes research in these areas and discusses targeting of Nrf2 in radiation-resistant cancer and Nrf2׳s role in mitigating acute radiation syndrome.
MeSH term(s)	Animals ; Cell Survival/physiology ; Cell Survival/radiation effects ; DNA Repair/physiology ; Humans ; NF-E2-Related Factor 2/metabolism ; Radiation Tolerance/physiology ; Radiation, Ionizing
Chemical Substances	NF-E2-Related Factor 2
Language	English
Publishing date	2015-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	807032-5
ISSN	1873-4596 ; 0891-5849
ISSN (online)	1873-4596
ISSN	0891-5849
DOI	10.1016/j.freeradbiomed.2015.04.035
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Article ; Online: Radiosensitization by enzalutamide for human prostate cancer is mediated through the DNA damage repair pathway.

Sekhar, Konjeti R / Wang, Jian / Freeman, Michael L / Kirschner, Austin N

PloS one

2019 Volume 14, Issue 4, Page(s) e0214670

Abstract: Radiation therapy is often combined with androgen deprivation therapy in the treatment of aggressive localized prostate cancer. However, castration-resistant disease may not respond to testosterone deprivation approaches. Enzalutamide is a second- ... ...

Abstract	Radiation therapy is often combined with androgen deprivation therapy in the treatment of aggressive localized prostate cancer. However, castration-resistant disease may not respond to testosterone deprivation approaches. Enzalutamide is a second-generation anti-androgen with high affinity and activity that is used for the treatment of metastatic disease. Although radiosensitization mechanisms are known to be mediated through androgen receptor activity, this project aims to uncover the detailed DNA damage repair factors influenced by enzalutamide using multiple models of androgen-sensitive (LNCaP) and castration-resistant human prostate cancer (22Rv1 and DU145). Enzalutamide is able to radiosensitize both androgen-dependent and androgen-independent human prostate cancer models in cell culture and xenografts in mice, as well as a treatment-resistant patient-derived xenograft. The enzalutamide-mediated mechanism of radiosensitization includes delay of DNA repair through temporal prolongation of the repair factor complexes and halting the cell cycle, which results in decreased colony survival. Altogether, these findings support the use of enzalutamide concurrently with radiotherapy to enhance the treatment efficacy for prostate cancer.
MeSH term(s)	Aged ; Animals ; Benzamides ; Cell Line, Tumor ; Cell Proliferation/drug effects ; DNA Damage/drug effects ; DNA Damage/genetics ; DNA Repair/drug effects ; DNA Repair/genetics ; Drug Resistance, Neoplasm/drug effects ; Drug Resistance, Neoplasm/genetics ; Drug Resistance, Neoplasm/radiation effects ; Humans ; Male ; Mice ; Mice, Nude ; Mice, Transgenic ; Nitriles ; Phenylthiohydantoin/analogs & derivatives ; Phenylthiohydantoin/pharmacology ; Phenylthiohydantoin/therapeutic use ; Prostatic Neoplasms/drug therapy ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/pathology ; Prostatic Neoplasms/radiotherapy ; Prostatic Neoplasms, Castration-Resistant/drug therapy ; Prostatic Neoplasms, Castration-Resistant/genetics ; Prostatic Neoplasms, Castration-Resistant/pathology ; Prostatic Neoplasms, Castration-Resistant/radiotherapy ; Radiation Tolerance/drug effects ; Radiation Tolerance/genetics ; Radiation-Sensitizing Agents/pharmacology ; Signal Transduction/drug effects ; Signal Transduction/genetics ; Xenograft Model Antitumor Assays
Chemical Substances	Benzamides ; Nitriles ; Radiation-Sensitizing Agents ; Phenylthiohydantoin (2010-15-3) ; enzalutamide (93T0T9GKNU)
Language	English
Publishing date	2019-04-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0214670
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Article ; Online: Integrative computational immunogenomic profiling of cortisol-secreting adrenocortical carcinoma.

Baechle, Jordan J / Hanna, David N / Sekhar, Konjeti R / Rathmell, Jeffrey C / Rathmell, W Kimryn / Baregamian, Naira

Journal of cellular and molecular medicine

2021 Volume 25, Issue 21, Page(s) 10061–10072

Abstract: Adrenocortical carcinoma (ACC) is a rare but highly aggressive malignancy. Nearly half of ACC tumours overproduce and secrete adrenal steroids. Excess cortisol secretion, in particular, has been associated with poor prognosis among ACC patients. ... ...

Abstract	Adrenocortical carcinoma (ACC) is a rare but highly aggressive malignancy. Nearly half of ACC tumours overproduce and secrete adrenal steroids. Excess cortisol secretion, in particular, has been associated with poor prognosis among ACC patients. Furthermore, recent immunotherapy clinical trials have demonstrated significant immunoresistance among cortisol-secreting ACC (CS-ACC) patients when compared to their non-cortisol-secreting (nonCS-ACC) counterparts. The immunosuppressive role of excess glucocorticoid therapies and hypersecretion is known; however, the impact of the cortisol hypersecretion on ACC tumour microenvironment (TME), immune expression profiles and immune cell responses remain largely undefined. In this study, we characterized the TME of ACC patients and compared the immunogenomic profiles of nonCS-ACC and CS-ACC tumours to assess the impact of differentially expressed genes (DEGs) by utilizing The Cancer Genome Atlas (TCGA) database. Immunogenomic comparison (CS- vs. nonCS-ACC tumour TMEs) demonstrated an immunosuppressive expression profile with a direct impact on patient survival. We identified several primary prognostic indicators and potential targets within ACC tumour immune landscape. Differentially expressed immune genes with prognostic significance provide additional insight into the understanding of potential contributory mechanisms underlying failure of initial immunotherapeutic trials and poor prognosis of patients with CS-ACC.
MeSH term(s)	Adrenal Cortex Neoplasms/etiology ; Adrenal Cortex Neoplasms/metabolism ; Adrenal Cortex Neoplasms/pathology ; Adrenocortical Carcinoma/etiology ; Adrenocortical Carcinoma/metabolism ; Adrenocortical Carcinoma/pathology ; Computational Biology/methods ; Databases, Genetic ; Disease Susceptibility ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Humans ; Hydrocortisone/metabolism ; Lymphocytes, Tumor-Infiltrating/immunology ; Lymphocytes, Tumor-Infiltrating/metabolism ; Lymphocytes, Tumor-Infiltrating/pathology ; Tumor-Associated Macrophages/immunology ; Tumor-Associated Macrophages/metabolism ; Tumor-Associated Macrophages/pathology
Chemical Substances	Hydrocortisone (WI4X0X7BPJ)
Language	English
Publishing date	2021-10-19
Publishing country	England
Document type	Journal Article
ZDB-ID	2074559-X
ISSN	1582-4934 ; 1582-4934 ; 1582-1838
ISSN (online)	1582-4934
ISSN	1582-4934 ; 1582-1838
DOI	10.1111/jcmm.16936
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Article ; Online: Targeting NPM1 in irradiated cells inhibits NPM1 binding to RAD51, RAD51 foci formation and radiosensitizes NSCLC.

Traver, Geri / Sekhar, Konjeti R / Crooks, Peter A / Keeney, Diane S / Freeman, Michael L

Cancer letters

2020 Volume 500, Page(s) 220–227

Abstract: The ability of chemo-radiation therapy to control locally advanced stage III non-small cell lung cancer (NSCLC) is poor. While addition of consolidation immunotherapy has improved outcomes in subsets of patients there is still an urgent need for new ... ...

Abstract	The ability of chemo-radiation therapy to control locally advanced stage III non-small cell lung cancer (NSCLC) is poor. While addition of consolidation immunotherapy has improved outcomes in subsets of patients there is still an urgent need for new therapeutic targets. Emerging research indicates that nucleophosmin1 (NPM1) is over-expressed in NSCLC, promotes tumor growth and that over-expression correlates with a lower survival probability. NPM1 is critical for APE1 base excision activity and for RAD51-mediated repair of DNA double strand breaks (DSBs). YTR107 is a small molecule radiation sensitizer that has been shown to bind to NPM1, suppressing pentamer formation. Here we show that in irradiated cells YTR107 inhibits SUMOylated NPM1 from associating with RAD51, RAD51 foci formation and repair of DSBs. YTR107 acts synergistically with the PARP1/2 inhibitor ABT 888 to increase replication stress and radiation-induced cell lethality. YTR107 was found to radiosensitize tumor initiating cells. Congruent with this knowledge, adding YTR107 to a fractionated irradiation regimen diminished NSCLC xenograft growth and increased overall survival. These data support the hypothesis that YTR107 represents a therapeutic target for control of NSCLC.
MeSH term(s)	Barbiturates/pharmacology ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/genetics ; Carcinoma, Non-Small-Cell Lung/pathology ; Carcinoma, Non-Small-Cell Lung/radiotherapy ; Cell Line, Tumor ; Cell Proliferation/drug effects ; DNA Breaks, Double-Stranded/radiation effects ; DNA Repair/drug effects ; DNA Repair/radiation effects ; DNA-(Apurinic or Apyrimidinic Site) Lyase/genetics ; Humans ; Indoles/pharmacology ; Neoplasm Recurrence, Local/drug therapy ; Neoplasm Recurrence, Local/genetics ; Neoplasm Recurrence, Local/pathology ; Neoplasm Recurrence, Local/radiotherapy ; Nuclear Proteins/genetics ; Poly (ADP-Ribose) Polymerase-1/antagonists & inhibitors ; Poly (ADP-Ribose) Polymerase-1/genetics ; Rad51 Recombinase/genetics ; Radiation Tolerance/drug effects ; Radiation-Sensitizing Agents/pharmacology ; Sumoylation/drug effects ; Sumoylation/radiation effects
Chemical Substances	5-((N-benzyl-1H-indol-3-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)trione ; Barbiturates ; Indoles ; Nuclear Proteins ; Radiation-Sensitizing Agents ; nucleophosmin (117896-08-9) ; Poly (ADP-Ribose) Polymerase-1 (EC 2.4.2.30) ; Rad51 Recombinase (EC 2.7.7.-) ; APEX1 protein, human (EC 4.2.99.18) ; DNA-(Apurinic or Apyrimidinic Site) Lyase (EC 4.2.99.18)
Language	English
Publishing date	2020-12-21
Publishing country	Ireland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	195674-7
ISSN	1872-7980 ; 0304-3835
ISSN (online)	1872-7980
ISSN	0304-3835
DOI	10.1016/j.canlet.2020.12.023
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Article ; Online: The Role of Nrf2 in the Response to Normal Tissue Radiation Injury.

Cameron, Brent D / Sekhar, Konjeti R / Ofori, Maxwell / Freeman, Michael L

Radiation research

2018 Volume 190, Issue 2, Page(s) 99–106

Abstract: The transcription factor Nrf2 is an important modulator of antioxidant and drug metabolism, carbohydrate and lipid metabolism, as well as heme and iron metabolism. Regulation of Nrf2 expression occurs transcriptionally and post-transcriptionally. Post- ... ...

Abstract	The transcription factor Nrf2 is an important modulator of antioxidant and drug metabolism, carbohydrate and lipid metabolism, as well as heme and iron metabolism. Regulation of Nrf2 expression occurs transcriptionally and post-transcriptionally. Post-transcriptional regulation entails ubiquitination followed by proteasome-dependent degradation. Additionally, Nrf2-mediated gene expression is subject to negative regulation by ATF3, Bach1 and cMyc. Nrf2-mediated gene expression is an important regulator of a cell's response to radiation. Although a majority of studies have shown that Nrf2 deficient cells are radiosensitized and Nrf2 over expression confers radioresistance, Nrf2's role in mediating the radiation response of crypt cells is controversial. The Nrf2 activator CDDO attenuates radiation-mediated crypt injury, whereas intestinal crypts in Nrf2 null mice are radiation resistant. Further investigation is needed in order to define the relationship between Nrf2 and radiation sensitivity in Lgr5+ and Bmi1+ cells that regulate regeneration of crypt stem cells. In hematopoietic compartments Nrf2 promotes the survival of irradiated osteoblasts that support long-term hematopoietic stem cell (LT-HSC) niches. Loss of Nrf2 in LT-HSCs increases stem cell intrinsic radiosensitivity, with the consequence of lowering the LD50
MeSH term(s)	Animals ; Hematopoietic System/radiation effects ; Humans ; Intestines/metabolism ; Intestines/radiation effects ; Lung/metabolism ; Lung/radiation effects ; NF-E2-Related Factor 2/metabolism ; Radiation Injuries/metabolism ; Radiation Injuries/pathology
Chemical Substances	NF-E2-Related Factor 2
Language	English
Publishing date	2018-05-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	80322-4
ISSN	1938-5404 ; 0033-7587
ISSN (online)	1938-5404
ISSN	0033-7587
DOI	10.1667/RR15059.1
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