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1.
Front Aging ; 4: 1270838, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37840813

RESUMEN

Since its initial discovery almost three decades ago, the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) has been shown to regulate a host of downstream transcriptional responses and play a critical role in preventing or promoting disease progression depending on the context. Critically, while the importance of proper nuclear factor erythroid 2-related factor 2 function has been demonstrated across a variety of pathological settings, the ability to progress NRF2-targeted therapeutics to clinic has remained frustratingly elusive. This is particularly true in the case of age-related pathologies, where nuclear factor erythroid 2-related factor 2 is a well-established mitigator of many of the observed pathogenic effects, yet options to target this pathway remain limited. Along these lines, loss of nuclear factor erythroid 2-related factor 2 function has clearly been shown to enhance neuropathological outcomes, with enhancing nuclear factor erythroid 2-related factor 2 pathway activation to prevent neurodegenerative/neurological disease progression continuing to be an active area of interest. One critical obstacle in generating successful therapeutics for brain-related pathologies is the ability of the compound to cross the blood brain barrier (BBB), which has also hampered the implementation of several promising nuclear factor erythroid 2-related factor 2 inducers. Another limitation is that many nuclear factor erythroid 2-related factor 2 activators have undesirable off-target effects due to their electrophilic nature. Despite these constraints, the field has continued to evolve, and several viable means of targeting nuclear factor erythroid 2-related factor 2 in a neuropathological context have emerged. In this perspective, we will briefly discuss the key findings and promising therapeutic options that have been discovered to date, as well as highlight emerging areas of NRF2-neurodegeneration research that provide hope for successfully targeting this pathway in the future.

2.
Water (Basel) ; 15(9)2023 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-37886432

RESUMEN

Arsenic is ubiquitous in soil and water environments and is consistently at the top of the Agency for Toxic Substances Disease Registry (ATSDR) substance priority list. It has been shown to induce toxicity even at low levels of exposure. One of the major routes of exposure to arsenic is through drinking water. This review presents current information related to the distribution of arsenic in the environment, the resultant impacts on human health, especially related to diabetes, which is one of the most prevalent chronic diseases, regulation of arsenic in drinking water, and approaches for treatment of arsenic in drinking water for both public utilities and private wells. Taken together, this information points out the existing challenges to understanding both the complex health impacts of arsenic and to implementing the treatment strategies needed to effectively reduce arsenic exposure at different scales.

4.
Redox Biol ; 65: 102839, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37573837

RESUMEN

p97 is a ubiquitin-targeted ATP-dependent segregase that regulates proteostasis, in addition to a variety of other cellular functions. Previously, we demonstrated that p97 negatively regulates NRF2 by extracting ubiquitylated NRF2 from the KEAP1-CUL3-RBX1 E3 ubiquitin ligase complex, facilitating proteasomal destruction. In the current study, we identified p97 as an NRF2-target gene that contains a functional ARE, indicating the presence of an NRF2-p97-NRF2 negative feedback loop that maintains redox homeostasis. Using CRISPR/Cas9 genome editing, we generated endogenous p97 ARE-mutated BEAS-2B cell lines. These p97 ARE-mutated cell lines exhibit altered expression of p97 and NRF2, as well as a compromised response to NRF2 inducers. Importantly, we also found a positive correlation between NRF2 activation and p97 expression in human cancer patients. Finally, using chronic arsenic-transformed cell lines, we demonstrated a synergistic effect of NRF2 and p97 inhibition in killing cancer cells with high NRF2 and p97 expression. Our study suggests dual upregulation of NRF2 and p97 occurs in certain types of cancers, suggesting that inhibition of both NRF2 and p97 could be a promising treatment strategy for stratified cancer patients.


Asunto(s)
Proteínas Portadoras , Factor 2 Relacionado con NF-E2 , Humanos , Proteínas Portadoras/metabolismo , Proteínas Cullin/metabolismo , Retroalimentación , Proteína 1 Asociada A ECH Tipo Kelch/genética , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo
5.
Nat Cell Biol ; 25(6): 798-799, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37291266
6.
Adv Pharmacol ; 96: 47-69, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36858779

RESUMEN

Arsenic is an environmental toxicant that significantly enhances the risk of developing disease, including several cancers. While the epidemiological evidence supporting increased cancer risk due to chronic arsenic exposure is strong, therapies tailored to treat exposed populations are lacking. This can be accredited in large part to the chronic nature and pleiotropic pathological effects associated with prolonged arsenic exposure. Despite this fact, several putative mediators of arsenic promotion of cancer have been identified. Among these, the critical transcription factor NRF2 has been shown to be a key mediator of arsenic's pro-carcinogenic effects. Importantly, the dependence of arsenic-transformed cancer cells on NRF2 upregulation exposes a targetable liability that could be utilized to treat arsenic-promoted cancers. In this chapter, we briefly introduce the "light" vs "dark" side of the NRF2 pathway. We then give a brief overview of arsenic metabolism, and discuss the epidemiological and experimental evidence that support arsenic promotion of different cancers, with a specific emphasis on mechanisms mediated by chronic, non-canonical activation of NRF2 (i.e., the "dark" side). Finally, we briefly highlight how the non-canonical NRF2 pathway plays a role in other arsenic-promoted diseases, as well as research directions that warrant further investigation.


Asunto(s)
Arsénico , Humanos , Factor 2 Relacionado con NF-E2 , Carcinogénesis
7.
Mol Cells ; 46(3): 165-175, 2023 Mar 31.
Artículo en Inglés | MEDLINE | ID: mdl-36994475

RESUMEN

The transcription factor Nrf2 was originally identified as a master regulator of redox homeostasis, as it governs the expression of a battery of genes involved in mitigating oxidative and electrophilic stress. However, the central role of Nrf2 in dictating multiple facets of the cellular stress response has defined the Nrf2 pathway as a general mediator of cell survival. Recent studies have indicated that Nrf2 regulates the expression of genes controlling ferroptosis, an ironand lipid peroxidation-dependent form of cell death. While Nrf2 was initially thought to have anti-ferroptotic function primarily through regulation of the antioxidant response, accumulating evidence has indicated that Nrf2 also exerts anti-ferroptotic effects via regulation of key aspects of iron and lipid metabolism. In this review, we will explore the emerging role of Nrf2 in mediating iron homeostasis and lipid peroxidation, where several Nrf2 target genes have been identified that encode critical proteins involved in these pathways. A better understanding of the mechanistic relationship between Nrf2 and ferroptosis, including how genetic and/or pharmacological manipulation of Nrf2 affect the ferroptotic response, should facilitate the development of new therapies that can be used to treat ferroptosis-associated diseases.


Asunto(s)
Antioxidantes , Factor 2 Relacionado con NF-E2 , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Muerte Celular , Hierro/metabolismo
8.
Sci Adv ; 9(5): eade9585, 2023 02 03.
Artículo en Inglés | MEDLINE | ID: mdl-36724221

RESUMEN

Enhancing the intracellular labile iron pool (LIP) represents a powerful, yet untapped strategy for driving ferroptotic death of cancer cells. Here, we show that NRF2 maintains iron homeostasis by controlling HERC2 (E3 ubiquitin ligase for NCOA4 and FBXL5) and VAMP8 (mediates autophagosome-lysosome fusion). NFE2L2/NRF2 knockout cells have low HERC2 expression, leading to a simultaneous increase in ferritin and NCOA4 and recruitment of apoferritin into the autophagosome. NFE2L2/NRF2 knockout cells also have low VAMP8 expression, which leads to ferritinophagy blockage. Therefore, deletion of NFE2L2/NRF2 results in apoferritin accumulation in the autophagosome, an elevated LIP, and enhanced sensitivity to ferroptosis. Concordantly, NRF2 levels correlate with HERC2 and VAMP8 in human ovarian cancer tissues, as well as ferroptosis resistance in a panel of ovarian cancer cell lines. Last, the feasibility of inhibiting NRF2 to increase the LIP and kill cancer cells via ferroptosis was demonstrated in preclinical models, signifying the impact of NRF2 inhibition in cancer treatment.


Asunto(s)
Ferroptosis , Neoplasias Ováricas , Humanos , Femenino , Ferroptosis/genética , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Apoferritinas , Hierro/metabolismo , Homeostasis , Ubiquitina-Proteína Ligasas/metabolismo , Proteínas R-SNARE/metabolismo
9.
Redox Biol ; 59: 102570, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36495698

RESUMEN

BACKGROUND AND AIMS: Caloric excess and sedentary lifestyles have led to an epidemic of obesity, metabolic syndrome, and non-alcoholic fatty liver disease (NAFLD). The objective of this study was to investigate the mechanisms underlying high fat diet (HFD)-induced NAFLD, and to explore NRF2 activation as a strategy to alleviate NAFLD. APPROACH AND RESULTS: Herein, we demonstrated that high fat diet (HFD) induced lipid peroxidation and ferroptosis, both of which could be alleviated by NRF2 upregulation. Mechanistically, HFD suppressed autophagosome biogenesis through AMPK- and AKT-mediated mTOR activation and decreased ATG7, resulting in KEAP1 stabilization and decreased NRF2 levels in mouse liver. Furthermore, ATG7 is required for HFD-induced NRF2 downregulation, as ATG7 deletion in Cre-inducible ATG7 knockout mice decreased NRF2 levels and enhanced ferroptosis, which was not further exacerbated by HFD. This finding was recapitulated in mouse hepatocytes, which showed a similar phenotype upon treatment with saturated fatty acids (SFAs) but not monounsaturated fatty acids (MUFAs). Finally, NRF2 activation blocked fatty acid (FA)-mediated NRF2 downregulation, lipid peroxidation, and ferroptosis. Importantly, the HFD-induced alterations were also observed in human fatty liver tissue samples. CONCLUSIONS: HFD-mediated autophagy inhibition, NRF2 suppression, and ferroptosis promotion are important molecular mechanisms of obesity-driven metabolic diseases. NRF2 activation counteracts HFD-mediated NRF2 suppression and ferroptotic cell death. In addition, SFA vs. MUFA regulation of NRF2 may underlie their harmful vs. beneficial effects. Our study reveals NRF2 as a key player in the development and progression of fatty liver disease and that NRF2 activation could serve as a potential therapeutic strategy.


Asunto(s)
Enfermedad del Hígado Graso no Alcohólico , Animales , Ratones , Humanos , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Autofagosomas/metabolismo , Ácidos Grasos/metabolismo , Obesidad/metabolismo , Muerte Celular , Dieta Alta en Grasa/efectos adversos , Ratones Endogámicos C57BL , Hígado/metabolismo , Metabolismo de los Lípidos
10.
Work ; 74(1): 137-151, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36214016

RESUMEN

BACKGROUND: The 2001 Feasibility Evaluation Checklist (FEC) is an assessment of work readiness for individuals with acquired brain injury (ABI). It establishes the integrity of basic safety, productivity, and interpersonal factors in neurorehabilitation and vocational settings. This study represents an effort to further develop the FEC to increase its clinical utility. OBJECTIVE: To redesign the FEC by conducting Item Response Theory (IRT) analyses on the study's results and combining those mathematical calibrations with clinical expert judgement. The result will be a new measure for use in clinical ABI neurorehabilitation and vocational settings: the Employment Feasibility Checklist (EFC). METHODS: Seven participants with ABI were administered a situational assessment on multiple occasions by occupational therapists in a community rehabilitation clinic. The FEC was used to assess the participant's performance across three areas of basic employment feasibility: safety, productivity, and interpersonal factors. Results were analyzed with IRT-Rasch analysis and then subjected to clinical expert judgment, resulting in adjustment recommendations for the FEC. RESULTS: In this scale development study, IRT analysis of results from 89 observation trials was combined with expert clinical judgment resulting in a redesigned tool with increased clinical utility for persons with ABI. The EFC is a 12-item observational rating scale for employment feasibility constructs of Productivity and Interpersonal Relations, with an additional six-item Workplace Safety subsection. CONCLUSION: The EFC is a mathematically calibrated tool designed to gauge feasibility for competitive employment in clients with ABI. The tool may be useful in clinical neurorehabilitation settings and vocational rehabilitation settings.


Asunto(s)
Lesiones Encefálicas , Reinserción al Trabajo , Humanos , Lista de Verificación , Estudios de Factibilidad , Empleo , Rehabilitación Vocacional/métodos , Lesiones Encefálicas/rehabilitación
11.
Diabetes ; 71(12): 2463-2476, 2022 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-36409792

RESUMEN

Despite decades of scientific effort, diabetes continues to represent an incredibly complex and difficult disease to treat. This is due in large part to the multifactorial nature of disease onset and progression and the multiple organ systems affected. An increasing body of scientific evidence indicates that a key mediator of diabetes progression is NRF2, a critical transcription factor that regulates redox, protein, and metabolic homeostasis. Importantly, while experimental studies have confirmed the critical nature of proper NRF2 function in preventing the onset of diabetic outcomes, we have only just begun to scratch the surface of understanding the mechanisms by which NRF2 modulates diabetes progression, particularly across different causative contexts. One reason for this is the contradictory nature of the current literature, which can often be accredited to model discrepancies, as well as whether NRF2 is activated in an acute or chronic manner. Furthermore, despite therapeutic promise, there are no current NRF2 activators in clinical trials for the treatment of patients with diabetes. In this review, we briefly introduce the transcriptional programs regulated by NRF2 as well as how NRF2 itself is regulated. We also review the current literature regarding NRF2 modulation of diabetic phenotypes across the different diabetes subtypes, including a brief discussion of contradictory results, as well as what is needed to progress the NRF2 diabetes field forward.


Asunto(s)
Diabetes Mellitus , Factor 2 Relacionado con NF-E2 , Humanos , Factor 2 Relacionado con NF-E2/metabolismo , Diabetes Mellitus/genética , Oxidación-Reducción , Homeostasis
12.
Front Aging ; 3: 812810, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35821809

RESUMEN

Mitochondrial dysfunction and metabolic decline are prevalent features of aging and age-related disorders, including neurodegeneration. Neurodegenerative diseases are associated with a progressive loss of metabolic homeostasis. This pathogenic decline in metabolism is the result of several factors, including decreased mitochondrial function, increased oxidative stress, inhibited autophagic flux, and altered metabolic substrate availability. One critical metabolite for maintaining neuronal function is glucose, which is utilized by the brain more than any other organ to meet its substantial metabolic demand. Enzymatic conversion of glucose into its downstream metabolites is critical for maintaining neuronal cell growth and overall metabolic homeostasis. Perturbation of glycolysis could significantly hinder neuronal metabolism by affecting key metabolic pathways. Here, we demonstrate that the glucose analogue 2-deoxyglucose (2DG) decreases cell viability, as well as both basal and maximal mitochondrial oxygen consumption in response to the neurotoxic lipid 4-hydroxynonenal (HNE), whereas glucose deprivation has a minimal effect. Furthermore, using a cell permeabilization assay we found that 2DG has a more pronounced effect on HNE-dependent inhibition of mitochondrial complex I and II than glucose deprivation. Importantly, these findings indicate that altered glucose utilization plays a critical role in dictating neuronal survival by regulating the mitochondrial response to electrophilic stress.

13.
Mol Oncol ; 16(8): 1714-1727, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35184380

RESUMEN

The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) is often highly expressed in non-small cell lung cancer (NSCLC). Through its target genes, NRF2 enhances cancer progression and chemo/radioresistance, leading to a poorer prognosis in patients with high NRF2 expression. In this study, we identified CHM-like Rab escort protein (CHML; encoding Rep2) as an NRF2 target gene with an antioxidant response element (ARE) in its promoter region (-1622 to -1612). Analysis of patient data curated by The Cancer Genome Atlas (TCGA) and Oncomine databases revealed that CHML mRNA expression was elevated in lung adenocarcinoma (LUAD) patient tumor tissues and correlated with decreased patient survival. Immunohistochemistry (IHC) analysis of normal versus lung cancer patient tissues revealed that Rep2 protein levels were higher in lung tumors compared with normal tissue, which also correlated with increased levels of NRF2. Importantly, siRNA-mediated knockdown of CHML/Rep2 in A549 NSCLC cells decreased their ability to proliferate. Mechanistically, Rep2 mediates mTOR function, as loss of Rep2 inhibited, whereas overexpression enhanced, mTOR translocation and activation at the lysosome. Our findings identify a novel NRF2-Rep2-dependent regulation of mTOR function.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Ácidos Grasos Insaturados , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares/patología , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo
14.
Artículo en Inglés | MEDLINE | ID: mdl-37779901

RESUMEN

Inorganic arsenic (iAs) exposure has been associated to various detrimental effects such as development of metabolic syndrome and type 2 diabetes via oxidative stress and induced prolonged activation of the NRF2 transcription factor. Such effects can be aggravated by poor dietary habits. The role of gut microbiota in promoting metabolic changes in response to arsenic has yet to be precisely defined. To address the complexity of the interactions between diet, NFE2L2/NRF2, and gut microbiota, we studied the chronic effects of iAs exposure in wild-type (WT) and Nrf2-/- mice fed normal (ND) vs. high-fat diet (HFD), on the gut microbial community in the context of hepatic metabolism. We demonstrate that all treatments and interactions influenced bacteria and metabolic profiles, with dietary differences causing a strong overlap of responses between the datasets. By identifying five metabolites of known microbial origin and following their fate across treatments, we provide examples on how gut microbial products can participate in the development of iAs and HFD-induced metabolic disease. Overall, our results underline the importance of the microbial community in driving gut-liver-cross talk during iAs and HFD exposure.

15.
J Med Chem ; 64(21): 15727-15746, 2021 11 11.
Artículo en Inglés | MEDLINE | ID: mdl-34676755

RESUMEN

Increased protein synthesis is a requirement for malignant growth, and as a result, translation has become a pharmaceutical target for cancer. The initiation of cap-dependent translation is enzymatically driven by the eukaryotic initiation factor (eIF)4A, an ATP-powered DEAD-box RNA-helicase that unwinds the messenger RNA secondary structure upstream of the start codon, enabling translation of downstream genes. A screen for inhibitors of eIF4A ATPase activity produced an intriguing hit that, surprisingly, was not ATP-competitive. A medicinal chemistry campaign produced the novel eIF4A inhibitor 28, which decreased BJAB Burkitt lymphoma cell viability. Biochemical and cellular studies, molecular docking, and functional assays uncovered that 28 is an RNA-competitive, ATP-uncompetitive inhibitor that engages a novel pocket in the RNA groove of eIF4A and inhibits unwinding activity by interfering with proper RNA binding and suppressing ATP hydrolysis. Inhibition of eIF4A through this unique mechanism may offer new strategies for targeting this promising intersection point of many oncogenic pathways.


Asunto(s)
Descubrimiento de Drogas , Factor 4F Eucariótico de Iniciación/antagonistas & inhibidores , Adenosina Trifosfatasas/antagonistas & inhibidores , Adenosina Trifosfatasas/metabolismo , Adenosina Trifosfato/metabolismo , Linfoma de Burkitt/patología , Línea Celular Tumoral , Humanos , Conformación de Ácido Nucleico , ARN Mensajero/química
16.
Aging Dis ; 12(4): 964-982, 2021 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-34221542

RESUMEN

Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a central regulator of cellular stress responses and its transcriptional activation promotes multiple cellular defense and survival mechanisms. The loss of NRF2 has been shown to increase oxidative and proteotoxic stress, two key pathological features of neurodegenerative disorders such as Parkinson's disease (PD). Moreover, compromised redox homeostasis and protein quality control can cause the accumulation of pathogenic proteins, including alpha-synuclein (α-Syn) which plays a key role in PD. However, despite this link, the precise mechanisms by which NRF2 may regulate PD pathology is not clear. In this study, we generated a humanized mouse model to study the importance of NRF2 in the context of α-Syn-driven neuropathology in PD. Specifically, we developed NRF2 knockout and wild-type mice that overexpress human α-Syn (hα-Syn+/Nrf2-/- and hα-Syn+/Nrf2+/+ respectively) and tested changes in their behavior through nest building, challenging beam, and open field tests at three months of age. Cellular and molecular alterations in α-Syn, including phosphorylation and subsequent oligomerization, as well as changes in oxidative stress, inflammation, and autophagy were also assessed across multiple brain regions. It was observed that although monomeric α-Syn levels did not change, compared to their wild-type counterparts, hα-Syn+/Nrf2-/- mice exhibited increased phosphorylation and oligomerization of α-Syn. This was associated with a loss of tyrosine hydroxylase expressing dopaminergic neurons in the substantia nigra, and more pronounced behavioral deficits reminiscent of early-stage PD, in the hα-Syn+/Nrf2-/- mice. Furthermore, hα-Syn+/Nrf2-/- mice showed significantly amplified oxidative stress, greater expression of inflammatory markers, and signs of increased autophagic burden, especially in the midbrain, striatum and cortical brain regions. These results support an important role for NRF2, early in PD progression. More broadly, it indicates NRF2 biology as fundamental to PD pathogenesis and suggests that targeting NRF2 activation may delay the onset and progression of PD.

17.
Cell Chem Biol ; 28(6): 741-742, 2021 06 17.
Artículo en Inglés | MEDLINE | ID: mdl-34143955

RESUMEN

In this issue of Cell Chemical Biology, Kuang et al. (2021) identify microsomal glutathione-S-transferase 1 (MGST1) as an NRF2 target gene that suppresses ferroptosis in pancreatic cancer cells. Mechanistically, MGST1 binds ALOX5 during ferroptosis induction, inhibiting lipid peroxide production. Thus, MGST1 could represent a viable therapeutic target for treating pancreatic cancer.


Asunto(s)
Ferroptosis , Personal Militar , Humanos , Factor 2 Relacionado con NF-E2/genética
18.
Semin Cancer Biol ; 76: 110-119, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34020028

RESUMEN

The complex role of NRF2 in the context of cancer continues to evolve. As a transcription factor, NRF2 regulates various genes involved in redox homeostasis, protein degradation, DNA repair, and xenobiotic metabolism. As such, NRF2 is critical in preserving cell function and viability, particularly during stress. Importantly, NRF2 itself is regulated via a variety of mechanisms, and the mode of NRF2 activation often dictates the duration of NRF2 signaling and its role in either preventing cancer initiation or promoting cancer progression. Herein, different modes of NRF2 regulation, including oxidative stress, autophagy dysfunction, protein-protein interactions, and epigenetics, as well as pharmacological modulators targeting this cascade in cancer, are explored. Specifically, how the timing and duration of these different mechanisms of NRF2 induction affect tumor initiation, progression, and metastasis are discussed. Additionally, progress in the discovery and development of NRF2 inhibitors for the treatment of NRF2-addicted cancers is highlighted, including modulators that inhibit specific NRF2 downstream targets. Overall, a better understanding of the intricate nature of NRF2 regulation in specific cancer contexts should facilitate the generation of novel therapeutics designed to not only prevent tumor initiation, but also halt progression and ultimately improve patient wellbeing and survival.


Asunto(s)
Factor 2 Relacionado con NF-E2/metabolismo , Neoplasias/metabolismo , Neoplasias/patología , Animales , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Regulación Neoplásica de la Expresión Génica/fisiología , Humanos
19.
Mol Metab ; 51: 101243, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-33933676

RESUMEN

OBJECTIVE: NRF2, a transcription factor that regulates cellular redox and metabolic homeostasis, plays a dual role in human disease. While it is well known that canonical intermittent NRF2 activation protects against diabetes-induced tissue damage, little is known regarding the effects of prolonged non-canonical NRF2 activation in diabetes. The goal of this study was to determine the role and mechanisms of prolonged NRF2 activation in arsenic diabetogenicity. METHODS: To test this, we utilized an integrated transcriptomic and metabolomic approach to assess diabetogenic changes in the livers of wild type, Nrf2-/-, p62-/-, or Nrf2-/-; p62-/- mice exposed to arsenic in the drinking water for 20 weeks. RESULTS: In contrast to canonical oxidative/electrophilic activation, prolonged non-canonical NRF2 activation via p62-mediated sequestration of KEAP1 increases carbohydrate flux through the polyol pathway, resulting in a pro-diabetic shift in glucose homeostasis. This p62- and NRF2-dependent increase in liver fructose metabolism and gluconeogenesis occurs through the upregulation of four novel NRF2 target genes, ketohexokinase (Khk), sorbitol dehydrogenase (Sord), triokinase/FMN cyclase (Tkfc), and hepatocyte nuclear factor 4 (Hnf4A). CONCLUSION: We demonstrate that NRF2 and p62 are essential for arsenic-mediated insulin resistance and glucose intolerance, revealing a pro-diabetic role for prolonged NRF2 activation in arsenic diabetogenesis.


Asunto(s)
Diabetes Mellitus Experimental/genética , Gluconeogénesis/genética , Resistencia a la Insulina/genética , Factor 2 Relacionado con NF-E2/metabolismo , Proteína Sequestosoma-1/metabolismo , Animales , Arsénico/toxicidad , Diabetes Mellitus Experimental/inducido químicamente , Perfilación de la Expresión Génica , Humanos , Proteína 1 Asociada A ECH Tipo Kelch/genética , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Metabolómica , Ratones , Factor 2 Relacionado con NF-E2/genética , Proteína Sequestosoma-1/genética
20.
Mol Carcinog ; 60(5): 331-341, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33684228

RESUMEN

Incidence of melanoma continues to rise in the United States with ~100,000 new cases diagnosed in 2019. While the 5-year survival rate of melanoma is 99% when localized, the rate of survival drops to 22.5% when distant disease is detected. As such, an area of great interest is understanding the mechanisms that promote melanoma metastasis so that better potential therapeutic targets can be discovered. Herein, we demonstrate that activation of NRF2 by FAM129B contributes to increased metastatic potential of BRAF V600E mutant melanoma cells. Specifically, FAM129B induces NRF2 by competing for Kelch-like ECH-associated protein 1 (KEAP1) binding (the negative regulator of NRF2) via an ETGE motif. Furthermore, we show that phosphorylation of FAM129B plays a role in mediating the interaction between FAM129B and KEAP1, as the phosphorylation status of FAM129B dictates its subcellular localization. When phosphorylated, FAM129B is found primarily in the cytosol where it can bind to KEAP1, but upon inhibition of mitogen-activated protein kinase kinase activity, FAM129B is localized to the cell membrane and no longer interacts with KEAP1. In BRAF V600E mutant melanoma, the mitogen-activated protein kinase pathway leads to hyperphosphorylation of FAM129B, and therefore FAM129B localizes to the cytosol, binds KEAP1, and upregulates NRF2. Importantly, genetic modulation or pharmacological inhibition that results in a decrease in FAM129B protein level or its phosphorylation decreases migration and invasion of mutant melanoma in an NRF2-dependent manner. Overall, these data indicate that phosphorylation of FAM129B plays a significant role in driving the metastatic potential of BRAF V600E melanoma via upregulation of the NRF2 signaling pathway.


Asunto(s)
Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Melanoma/patología , Factor 2 Relacionado con NF-E2/metabolismo , Fosfoproteínas/metabolismo , Proteínas Proto-Oncogénicas B-raf/genética , Sitios de Unión , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Citosol/metabolismo , Células HEK293 , Humanos , Melanoma/genética , Melanoma/metabolismo , Mutación , Factor 2 Relacionado con NF-E2/química , Fosforilación
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