|
1
|
Pacheco-Garcia JL, Cagiada M, Tienne-Matos K, Salido E, Lindorff-Larsen K, L. Pey A. Effect of naturally-occurring mutations on the stability and function of cancer-associated NQO1: Comparison of experiments and computation. Front Mol Biosci 2022; 9:1063620. [PMID: 36504709 PMCID: PMC9730889 DOI: 10.3389/fmolb.2022.1063620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 11/03/2022] [Indexed: 11/25/2022] Open
Abstract
Recent advances in DNA sequencing technologies are revealing a large individual variability of the human genome. Our capacity to establish genotype-phenotype correlations in such large-scale is, however, limited. This task is particularly challenging due to the multifunctional nature of many proteins. Here we describe an extensive analysis of the stability and function of naturally-occurring variants (found in the COSMIC and gnomAD databases) of the cancer-associated human NAD(P)H:quinone oxidoreductase 1 (NQO1). First, we performed in silico saturation mutagenesis studies (>5,000 substitutions) aimed to identify regions in NQO1 important for stability and function. We then experimentally characterized twenty-two naturally-occurring variants in terms of protein levels during bacterial expression, solubility, thermal stability, and coenzyme binding. These studies showed a good overall correlation between experimental analysis and computational predictions; also the magnitude of the effects of the substitutions are similarly distributed in variants from the COSMIC and gnomAD databases. Outliers in these experimental-computational genotype-phenotype correlations remain, and we discuss these on the grounds and limitations of our approaches. Our work represents a further step to characterize the mutational landscape of NQO1 in the human genome and may help to improve high-throughput in silico tools for genotype-phenotype correlations in this multifunctional protein associated with disease.
Collapse
Affiliation(s)
| | - Matteo Cagiada
- Department of Biology, Linderstrøm-Lang Centre for Protein Science, University of Copenhagen, Copenhagen, Denmark
| | | | - Eduardo Salido
- Center for Rare Diseases (CIBERER), Hospital Universitario de Canarias, Universidad de la Laguna, La Laguna, TenerifeTenerife, Spain
| | - Kresten Lindorff-Larsen
- Department of Biology, Linderstrøm-Lang Centre for Protein Science, University of Copenhagen, Copenhagen, Denmark
| | - Angel L. Pey
- Departamento de Química Física, Unidad de Excelencia en Química Aplicada a Biomedicina y Medioambiente e Instituto de Biotecnología, Universidad de Granada, Granada, Spain,*Correspondence: Angel L. Pey,
| |
Collapse
|
|
2
|
Liu JJ, Xu Y, Chen S, Hao CF, Liang J, Li ZL. The mechanism of Yinchenhao decoction in treating obstructive-jaundice-induced liver injury based on Nrf2 signaling pathway. World J Gastroenterol 2022; 28:4635-4648. [PMID: 36157920 PMCID: PMC9476870 DOI: 10.3748/wjg.v28.i32.4635] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 06/08/2022] [Accepted: 06/24/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Obstructive jaundice (OJ) is caused by bile excretion disorder after partial or complete bile duct obstruction. It may cause liver injury through various mechanisms. Traditional Chinese medicine (TCM) has a lot of advantages in treating OJ. The recovery of liver function can be accelerated by combining Chinese medicine treatment with existing clinical practice. Yinchenhao decoction (YCHD), a TCM formula, has been used to treat jaundice. Although much progress has been made in recent years in understanding the mechanism of YCHD in treating OJ-induced liver injury, it is still not clear. AIM To investigate chemical components of YCHD that are effective in the treatment of OJ and predict the mechanism of YCHD. METHODS The active components and putative targets of YCHD were predicted using a network pharmacology approach. Gene Ontology biological process and Kyoto Encyclopedia of Genes and Genomes path enrichment analysis were carried out by cluster profile. We predicted the biological processes, possible targets, and associated signaling pathways that YCHD may involve in the treatment of OJ. Thirty male Sprague-Dawley rats were randomly divided into three groups, each consisting of 10 rats: the sham group (Group S), the OJ model group (Group M), and the YCHD-treated group (Group Y). The sham group only received laparotomy. The OJ model was established by ligating the common bile duct twice in Groups M and Y. For 1 wk, rats in Group Y were given a gavage of YCHD (3.6 mL/kg) twice daily, whereas rats in Groups S and M were given the same amount of physiological saline after intragastric administration daily. After 7 d, all rats were killed, and the liver and blood samples were collected for histopathological and biochemical examinations. Total bilirubin (TBIL), direct bilirubin (DBIL), alanine aminotransferase (ALT), and aspartate transaminase (AST) levels in the blood samples were detected. The gene expression levels of inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS), and the nucleus positive rate of NF-E2 related factor 2 (Nrf2) protein were measured. Western blot analyses were used to detect the protein and gene expression levels of Nrf2, Kelch-like ECH-associated protein 1, NAD(P)H quinone dehydrogenase 1 (NQO1), and glutathione-S-transferase (GST) in the liver tissues. One-way analysis of variance was used to evaluate the statistical differences using the statistical package for the social sciences 23.0 software. Intergroup comparisons were followed by the least significant difference test and Dunnett's test. RESULTS The effects of YCHD on OJ involve biological processes such as DNA transcription factor binding, RNA polymerase II specific regulation, DNA binding transcriptional activator activity, and nuclear receptor activity. The protective effects of YCHD against OJ were closely related to 20 pathways, including the hepatitis-B, the mitogen-activated protein kinase, the phosphatidylinositol 3-kinase/protein kinase B, and tumor necrosis factor signaling pathways. YCHD alleviated the swelling and necrosis of hepatocytes. Following YCHD treatment, the serum levels of TBIL (176.39 ± 17.03 μmol/L vs 132.23 ± 13.88 μmol/L, P < 0.01), DBIL (141.41 ± 14.66 μmol/L vs 106.43 ± 10.88 μmol/L, P < 0.01), ALT (332.07 ± 34.34 U/L vs 269.97 ± 24.78 U/L, P < 0.05), and AST (411.44 ± 47.64 U/L vs 305.47 ± 29.36 U/L, P < 0.01) decreased. YCHD promoted the translocation of Nrf2 into the nucleus (12.78 ± 0.99 % vs 60.77 ± 1.90 %, P < 0.001). After YCHD treatment, we found a decrease in iNOS (0.30 ± 0.02 vs 0.20 ± 0.02, P < 0.001) and an increase in eNOS (0.18 ± 0.02 vs 0.32 ± 0.02, P < 0.001). Meanwhile, in OJ rats, YCHD increased the expressions of Nrf2 (0.57 ± 0.03 vs 1.18 ± 0.10, P < 0.001), NQO1 (0.13 ± 0.09 vs 1.19 ± 0.07, P < 0.001), and GST (0.12 ± 0.02 vs 0.50 ± 0.05, P < 0.001), implying that the potential mechanism of YCHD against OJ-induced liver injury was the upregulation of the Nrf2 signaling pathway. CONCLUSION OJ-induced liver injury is associated with the Nrf2 signaling pathway. YCHD can reduce liver injury and oxidative damage by upregulating the Nrf2 pathway.
Collapse
Affiliation(s)
- Jun-Jian Liu
- The Second Department of Hepatobiliary and Pancreatic Surgery, Tianjin Medical University NanKai Hospital, Tianjin 300102, China
| | - Yan Xu
- Graduate School, Tianjin Medical University, Tianjin 3000070, China
| | - Shuai Chen
- Department of Thoracic Surgery, Xuzhou City Hospital of Traditional Chinese Medicine, Xuzhou 221000, Jiangsu Province, China
| | - Cheng-Fei Hao
- The Second Department of Hepatobiliary and Pancreatic Surgery, Tianjin Medical University NanKai Hospital, Tianjin 300102, China
| | - Jing Liang
- School of Foreign Languages, Chengdu University of Traditional Chinese Medicine, Chengdu 610000, Sichuan Province, China
| | - Zhong-Lian Li
- The Second Department of Hepatobiliary and Pancreatic Surgery, Tianjin Medical University NanKai Hospital, Tianjin 300102, China
| |
Collapse
|
|
3
|
Preethi S, Arthiga K, Patil AB, Spandana A, Jain V. Review on NAD(P)H dehydrogenase quinone 1 (NQO1) pathway. Mol Biol Rep 2022; 49:8907-8924. [PMID: 35347544 DOI: 10.1007/s11033-022-07369-2] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Accepted: 03/11/2022] [Indexed: 12/14/2022]
Abstract
NQO1 is an enzyme present in humans which is encoded by NQO1 gene. It is a protective antioxidant agent, versatile cytoprotective agent and regulates the oxidative stresses of chromatin binding proteins for DNA damage in cancer cells. The oxidization of cellular pyridine nucleotides causes structural alterations to NQO1 and changes in its capacity to binding of proteins. A strategy based on NQO1 to have protective effect against cancer was developed by organic components to enhance NQO1 expression. The quinone derivative compounds like mitomycin C, RH1, E09 (Apaziquone) and β-lapachone causes cell death by NQO1 reduction of two electrons. It was also known to be overexpressed in various tumor cells of breast, lung, cervix, pancreas and colon when it was compared with normal cells in humans. The mechanism of NQO1 by the reduction of FAD by NADPH to form FADH2 is by two ways to inhibit cancer cell development such as suppression of carcinogenic metabolic activation and prevention of carcinogen formation. The NQO1 exhibit suppression of chemical-mediated carcinogenesis by various properties of NQO1 which includes, detoxification of quinone scavenger of superoxide anion radical, antioxidant enzyme, protein stabilizer. This review outlines the NQO1 structure, mechanism of action to inhibit the cancer cell, functions of NQO1 against oxidative stress, drugs acting on NQO1 pathways, clinical significance.
Collapse
Affiliation(s)
- S Preethi
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Sri Shivarathreeshwara Nagar, Mysuru, Karnataka, 570015, India
| | - K Arthiga
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Sri Shivarathreeshwara Nagar, Mysuru, Karnataka, 570015, India
| | - Amit B Patil
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Sri Shivarathreeshwara Nagar, Mysuru, Karnataka, 570015, India
| | - Asha Spandana
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Sri Shivarathreeshwara Nagar, Mysuru, Karnataka, 570015, India
| | - Vikas Jain
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Sri Shivarathreeshwara Nagar, Mysuru, Karnataka, 570015, India.
| |
Collapse
|
|
4
|
Okumura N, Ito T, Degawa T, Moriyama M, Moriyama H. Royal Jelly Protects against Epidermal Stress through Upregulation of the NQO1 Expression. Int J Mol Sci 2021; 22:12973. [PMID: 34884772 PMCID: PMC8657709 DOI: 10.3390/ijms222312973] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 11/24/2021] [Accepted: 11/29/2021] [Indexed: 12/15/2022] Open
Abstract
Royal jelly (RJ) is secreted by honeybees and has been used as an apitherapy to obtain healthy skin since ancient times. However, the mechanism of the protective effects of RJ against skin aging and skin diseases caused by skin stress and its components have not been clarified. In this study, we attempted to understand the effect of RJ on epidermal function and observed that NAD(P)H quinone dehydrogenase 1 (NQO1) is significantly induced by RJ in keratinocytes. The expression of NQO1 was also increased in the 3D epidermal skin model. NQO1 is involved in antioxidation and detoxification metabolism, and we found that RJ protects against the epidermal stress caused by UVB and menadione through the upregulation of NQO1. We identified 10-hydroxy-2-decenoic acid (10H2DA), a major fatty acid in RJ, as an active compound in this reaction as it induced the expression of NQO1 and protected the skin against oxidative stress. We demonstrated that the protective effect of RJ against epidermal stress is mediated through the upregulation of NQO1 by 10H2DA.
Collapse
Affiliation(s)
- Nobuaki Okumura
- Institute for Bee Products and Health Science, Yamada Bee Company Inc., Tomata-gun, Okayama 708-0393, Japan; (T.I.); (T.D.)
- Group Cosmetic Central Laboratory, Yamada Bee Company Inc., Shinagawa, Tokyo 104-0004, Japan
| | - Takashi Ito
- Institute for Bee Products and Health Science, Yamada Bee Company Inc., Tomata-gun, Okayama 708-0393, Japan; (T.I.); (T.D.)
| | - Tomomi Degawa
- Institute for Bee Products and Health Science, Yamada Bee Company Inc., Tomata-gun, Okayama 708-0393, Japan; (T.I.); (T.D.)
- Group Cosmetic Central Laboratory, Yamada Bee Company Inc., Shinagawa, Tokyo 104-0004, Japan
| | - Mariko Moriyama
- Pharmaceutical Research and Technology Institute, Kindai University, Higashi-Osaka, Osaka 577-8502, Japan; (M.M.); (H.M.)
| | - Hiroyuki Moriyama
- Pharmaceutical Research and Technology Institute, Kindai University, Higashi-Osaka, Osaka 577-8502, Japan; (M.M.); (H.M.)
| |
Collapse
|
|
5
|
Lee WS, Ham W, Kim J. Roles of NAD(P)H:quinone Oxidoreductase 1 in Diverse Diseases. Life (Basel) 2021; 11:life11121301. [PMID: 34947831 PMCID: PMC8703842 DOI: 10.3390/life11121301] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 11/15/2021] [Accepted: 11/18/2021] [Indexed: 01/07/2023] Open
Abstract
NAD(P)H:quinone oxidoreductase (NQO) is an antioxidant flavoprotein that catalyzes the reduction of highly reactive quinone metabolites by employing NAD(P)H as an electron donor. There are two NQO enzymes—NQO1 and NQO2—in mammalian systems. In particular, NQO1 exerts many biological activities, including antioxidant activities, anti-inflammatory effects, and interactions with tumor suppressors. Moreover, several recent studies have revealed the promising roles of NQO1 in protecting against cardiovascular damage and related diseases, such as dyslipidemia, atherosclerosis, insulin resistance, and metabolic syndrome. In this review, we discuss recent developments in the molecular regulation and biochemical properties of NQO1, and describe the potential beneficial roles of NQO1 in diseases associated with oxidative stress.
Collapse
Affiliation(s)
- Wang-Soo Lee
- Division of Cardiology, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul 06974, Korea
- Correspondence: (W.-S.L.); (J.K.); Tel.: +82-2-6299-1419 (W.-S.L.); +82-2-6299-1397 (J.K.)
| | - Woojin Ham
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul 06974, Korea;
| | - Jaetaek Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul 06974, Korea;
- Correspondence: (W.-S.L.); (J.K.); Tel.: +82-2-6299-1419 (W.-S.L.); +82-2-6299-1397 (J.K.)
| |
Collapse
|
|
6
|
Long noncoding RNA TUG1 regulates prostate cancer cell proliferation, invasion and migration via the Nrf2 signaling axis. Pathol Res Pract 2020; 216:152851. [PMID: 32057513 DOI: 10.1016/j.prp.2020.152851] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 01/03/2020] [Accepted: 02/04/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND Long noncoding RNAs (lncRNAs) have been identified to modulate the development and progression of prostate cancer (PCa) via the regulation of their target genes. However, the biological function underlying the effect of lncRNA TUG1 in PCa remains unclear. METHODS Reverse transcription-quantitative polymerase chain reaction (qRT-PCR) and Western blotting analysis were used to assess the mRNA expression of TUG1 and protein expression levels of Nrf2 pathway members, respectively. The migration, invasion, and proliferation abilities of cells were assessed by the wound-healing, Transwell migration/invasion, and CCK8 assays, respectively. RESULTS TUG1 was strikingly upregulated in PCa cells compared with non-tumorigenic human prostate epithelial cells. The LncTar Web Server, which is a bioinformatics tool, was used to predict the target association between TUG1 and Nrf2. Moreover, the expression of TUG1 showed a strikingly positive correlation with that of Nrf2 in TCGA PCa RNA-Seq data (r = 0.26,P = 4.63E-09). Subsequently, inhibition of TUG1 using siRNA resulted in deceased proliferation, migration, and invasion of PCa cells; however, these effects were reversed by treatment with oltipraz (an activator of Nrf2). Finally, we evaluated the Nrf2 pathway to reveal the underlying mechanism of TUG1 in PCa cells, and found that TUG1 knockdown decreased the protein expression of Nrf2 downstream members (e.g., HO-1, FTH1, and NQO1). CONCLUSIONS LncRNA TUG1 plays an oncogenic role in human PCa cells by promoting the cell proliferation and invasion in PCa cell lines, at least partly via the Nrf2 signaling pathway.
Collapse
|
|
7
|
Dimri M, Humphries A, Laknaur A, Elattar S, Lee TJ, Sharma A, Kolhe R, Satyanarayana A. NAD(P)H Quinone Dehydrogenase 1 Ablation Inhibits Activation of the Phosphoinositide 3-Kinase/Akt Serine/Threonine Kinase and Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Pathways and Blocks Metabolic Adaptation in Hepatocellular Carcinoma. Hepatology 2020; 71:549-568. [PMID: 31215069 PMCID: PMC6920612 DOI: 10.1002/hep.30818] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Accepted: 06/13/2019] [Indexed: 12/12/2022]
Abstract
Cancer cells undergo metabolic adaptation to sustain uncontrolled proliferation. Aerobic glycolysis and glutaminolysis are two of the most essential characteristics of cancer metabolic reprogramming. Hyperactivated phosphoinositide 3-kinase (PI3K)/Akt serine/threonine kinase (Akt) and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathways play central roles in cancer cell metabolic adaptation given that their downstream effectors, such as Akt and c-Myc, control most of the glycolytic and glutaminolysis genes. Here, we report that the cytosolic flavoprotein, NAD(P)H quinone dehydrogenase 1 (Nqo1), is strongly overexpressed in mouse and human hepatocellular carcinoma (HCC). Knockdown of Nqo1 enhanced activity of the serine/threonine phosphatase, protein phosphatase 2A, which operates at the intersection of the PI3K/Akt and MAPK/ERK pathways and dephosphorylates and inactivates pyruvate dehydrogenase kinase 1, Akt, Raf, mitogen-activated protein kinase kinase, and ERK1/2. Nqo1 ablation also induced the expression of phosphatase and tensin homolog, a dual protein/lipid phosphatase that blocks PI3K/Akt signaling, through the ERK/cAMP-responsive element-binding protein/c-Jun pathway. Together, Nqo1 ablation triggered simultaneous inhibition of the PI3K/Akt and MAPK/ERK pathways, suppressed the expression of glycolysis and glutaminolysis genes and blocked metabolic adaptation in liver cancer cells. Conversely, Nqo1 overexpression caused hyperactivation of the PI3K/Akt and MAPK/ERK pathways and promoted metabolic adaptation. Conclusion: In conclusion, Nqo1 functions as an upstream activator of both the PI3K/Akt and MAPK/ERK pathways in liver cancer cells, and Nqo1 ablation blocked metabolic adaptation and inhibited liver cancer cell proliferation and HCC growth in mice. Therefore, our results suggest that Nqo1 may function as a therapeutic target to inhibit liver cancer cell proliferation and inhibit HCC.
Collapse
Affiliation(s)
- Manali Dimri
- Department of Biochemistry and Molecular Biology, Molecular Oncology & Biomarkers Program, Georgia Cancer Center, Augusta University, Room-CN3150, 1410 Laney Walker Blvd., Augusta, GA 30912
| | - Ashley Humphries
- Department of Biochemistry and Molecular Biology, Molecular Oncology & Biomarkers Program, Georgia Cancer Center, Augusta University, Room-CN3150, 1410 Laney Walker Blvd., Augusta, GA 30912
| | - Archana Laknaur
- Department of Biochemistry and Molecular Biology, Molecular Oncology & Biomarkers Program, Georgia Cancer Center, Augusta University, Room-CN3150, 1410 Laney Walker Blvd., Augusta, GA 30912
| | - Sawsan Elattar
- Department of Biochemistry and Molecular Biology, Molecular Oncology & Biomarkers Program, Georgia Cancer Center, Augusta University, Room-CN3150, 1410 Laney Walker Blvd., Augusta, GA 30912
| | - Tae Jin Lee
- Center for Biotechnology and Genomic Medicine, Department of Population Health Sciences, Augusta University, GA, 30912
| | - Ashok Sharma
- Center for Biotechnology and Genomic Medicine, Department of Population Health Sciences, Augusta University, GA, 30912
| | - Ravindra Kolhe
- Department of Pathology, Section of Anatomic Pathology, Augusta University, Augusta, GA 30912
| | - Ande Satyanarayana
- Department of Biochemistry and Molecular Biology, Molecular Oncology & Biomarkers Program, Georgia Cancer Center, Augusta University, Room-CN3150, 1410 Laney Walker Blvd., Augusta, GA 30912
| |
Collapse
|
|
8
|
Diaz-Ruiz A, Di Francesco A, Carboneau BA, Levan SR, Pearson KJ, Price NL, Ward TM, Bernier M, de Cabo R, Mercken EM. Benefits of Caloric Restriction in Longevity and Chemical-Induced Tumorigenesis Are Transmitted Independent of NQO1. J Gerontol A Biol Sci Med Sci 2019; 74:155-162. [PMID: 29733330 DOI: 10.1093/gerona/gly112] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Accepted: 05/02/2018] [Indexed: 12/22/2022] Open
Abstract
Caloric restriction (CR) is the most potent nonpharmacological intervention known to both protect against carcinogenesis and delay aging in laboratory animals. There is a growing number of anticarcinogens and CR mimetics that activate NAD(P)H:quinone oxidoreductase 1 (NQO1). We have previously shown that NQO1, an antioxidant enzyme that acts as an energy sensor through modulation of intracellular redox and metabolic state, is upregulated by CR. Here, we used NQO1-knockout (KO) mice to investigate the role of NQO1 in both the aging process and tumor susceptibility, specifically in the context of CR. We found that NQO1 is not essential for the beneficial effects of CR on glucose homeostasis, physical performance, metabolic flexibility, life-span extension, and (unlike our previously observation with Nrf2) chemical-induced tumorigenesis.
Collapse
Affiliation(s)
- Alberto Diaz-Ruiz
- Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland.,Nutritional Interventions Group, Precision Nutrition and Aging, Institute IMDEA Food, Madrid, Spain
| | - Andrea Di Francesco
- Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland
| | - Bethany A Carboneau
- Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland
| | - Sophia R Levan
- Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland
| | - Kevin J Pearson
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington
| | - Nathan L Price
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT.,Integrative Cell Signaling and Neurobiology of Metabolism Program, Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT
| | - Theresa M Ward
- Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland
| | - Michel Bernier
- Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland
| | - Rafael de Cabo
- Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland.,Nutritional Interventions Group, Precision Nutrition and Aging, Institute IMDEA Food, Madrid, Spain
| | - Evi M Mercken
- Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland
| |
Collapse
|
|
9
|
Dendrobium Officinale Polysaccharides Protect against MNNG-Induced PLGC in Rats via Activating the NRF2 and Antioxidant Enzymes HO-1 and NQO-1. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:9310245. [PMID: 31281597 PMCID: PMC6589278 DOI: 10.1155/2019/9310245] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Accepted: 01/29/2019] [Indexed: 12/11/2022]
Abstract
Dendrobium officinale polysaccharides (DOP) are the main effective ingredient in Dendrobium officinale. Nuclear factor erythroid 2-related factor 2 (NRF2) signaling is regarded as an important way to mitigate the effects of reactive oxygen species (ROS) damage and inhibit gastric cancer progress. This study introduces a previously unknown effect of DOP on precancerous lesions of gastric cancer (PLGC). The mechanism discussed herein is based on the NRF2 signal pathway as well as its downstream antioxidant enzymes heme oxygenase-1 (HO-1) and NADPH quinone oxidoreductase-1 (NQO-1). DOP was prepared by the alcohol deposition method, and its molecular weight was determined using High-Performance Gel-Permeation Chromatography (HPGPC). Sixty male rats were randomly divided into five groups: normal control group (NC), PLGC model group (PLGC), model treated with low dose (2.4 g/kg) of DOP (L-DOP), model treated with middle dose (4.8 g/kg) of DOP (M-DOP), and model treated with high dose (9.6 g/kg) of DOP (H-DOP). DOP was orally administered to rats for 15 consecutive days prior to the start of a seven-month course of 1-methyl-3-nitro-1-nitrosoguanidine (MNNG) exposure. Histological evaluation was observed by hematoxylin and eosin (HE) and alcian blue/periodic acid-Schiff (AB-PAS) staining. Alanine aminotransferase (ALT), aspartate transaminase (AST), serum creatinine (Scr), serum uric acid (UA), blood urea nitrogen (BUN), and HE staining were detected for liver and kidney function. The level of 8-hydroxy-deoxyguanosine (8-OHdG) in serum was detected by kits. The NRF2 protein expression was detected by immunohistochemistry, and western blotting was utilized to compare differential protein expression levels among cytoplasmic and nuclear cell fractions. Expression levels of antioxidant enzymes heme oxygenase 1 (HO-1), Glutamate-Cysteine Ligase Catalytic Subunit (GCLC), Glutamate-Cysteine Ligase Modifier Subunit (GCLM), and NAD(P)H: quinone oxidoreductase-1 (NQO-1) were analyzed by reverse transcriptase polymerase chain reaction (RT-PCR); furthermore, the protein expression of NRF2, HO-1, and NQO-1 was detected by western blotting. The results showed that the average content of DOP is 83%, and its molecular weight is mainly contained within 3500 and 1000000. The H-DOP experimental group exhibited noticeable weight gain after seven months, reduced intestinal metaplasia, and made the atypical hyperplasia to be kept in moderate or mild degree. Data also showed DOP to be capable of decreasing levels of ALT, UA, and BUN, all of which had been elevated following the appearance of MNNG-induced PLGCs. DOP was also seen to reduce the expression of 8-OHdG and promote the expression of NRF2 in the gastric mucosa. Furthermore, RT-PCR and western blotting results showed that DOP upregulated the gene and protein expression of HO-1 and NQO-1. These findings show that DOP prevents MNNG-induced PLGC along with subsequent liver and kidney damage. The protective effects of DOP are associated with the reduction of 8-OHdG levels as well as the activation of the NRF2 pathway and its related antioxidant enzymes, HO-1 and NQO-1.
Collapse
|
|
10
|
Diaz‐Ruiz A, Lanasa M, Garcia J, Mora H, Fan F, Martin‐Montalvo A, Di Francesco A, Calvo‐Rubio M, Salvador‐Pascual A, Aon MA, Fishbein KW, Pearson KJ, Villalba JM, Navas P, Bernier M, de Cabo R. Overexpression of CYB5R3 and NQO1, two NAD + -producing enzymes, mimics aspects of caloric restriction. Aging Cell 2018; 17:e12767. [PMID: 29706024 PMCID: PMC6052403 DOI: 10.1111/acel.12767] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/18/2018] [Indexed: 12/19/2022] Open
Abstract
Calorie restriction (CR) is one of the most robust means to improve health and survival in model organisms. CR imposes a metabolic program that leads to increased stress resistance and delayed onset of chronic diseases, including cancer. In rodents, CR induces the upregulation of two NADH-dehydrogenases, namely NAD(P)H:quinone oxidoreductase 1 (Nqo1) and cytochrome b5 reductase 3 (Cyb5r3), which provide electrons for energy metabolism. It has been proposed that this upregulation may be responsible for some of the beneficial effects of CR, and defects in their activity are linked to aging and several age-associated diseases. However, it is unclear whether changes in metabolic homeostasis solely through upregulation of these NADH-dehydrogenases have a positive impact on health and survival. We generated a mouse that overexpresses both metabolic enzymes leading to phenotypes that resemble aspects of CR including a modest increase in lifespan, greater physical performance, a decrease in chronic inflammation, and, importantly, protection against carcinogenesis, one of the main hallmarks of CR. Furthermore, these animals showed an enhancement of metabolic flexibility and a significant upregulation of the NAD+ /sirtuin pathway. The results highlight the importance of these NAD+ producers for the promotion of health and extended lifespan.
Collapse
Affiliation(s)
- Alberto Diaz‐Ruiz
- Translational Gerontology BranchNational Institute on AgingNational Institutes of HealthBaltimoreMDUSA
- Nutritional Interventions Group, Precision Nutrition and AgingInstitute IMDEA FoodMadridSpain
| | - Michael Lanasa
- Translational Gerontology BranchNational Institute on AgingNational Institutes of HealthBaltimoreMDUSA
| | - Joseph Garcia
- Translational Gerontology BranchNational Institute on AgingNational Institutes of HealthBaltimoreMDUSA
| | - Hector Mora
- Translational Gerontology BranchNational Institute on AgingNational Institutes of HealthBaltimoreMDUSA
| | - Frances Fan
- Translational Gerontology BranchNational Institute on AgingNational Institutes of HealthBaltimoreMDUSA
| | - Alejandro Martin‐Montalvo
- Translational Gerontology BranchNational Institute on AgingNational Institutes of HealthBaltimoreMDUSA
| | - Andrea Di Francesco
- Translational Gerontology BranchNational Institute on AgingNational Institutes of HealthBaltimoreMDUSA
| | - Miguel Calvo‐Rubio
- Department of Cell Biology, Physiology and ImmunologyAgrifood Campus of International Excellence, ceiA3University of CórdobaCórdobaSpain
| | - Andrea Salvador‐Pascual
- Department of PhysiologyFundación Investigación Hospital Clínico Universitario/INCLIVAUniversity of ValenciaValenciaSpain
| | - Miguel A. Aon
- Laboratory of Cardiovascular ScienceNational Institute on AgingNational Institutes of HealthBaltimoreMDUSA
| | - Kenneth W. Fishbein
- Laboratory of Clinical InvestigationNational Institute on AgingNational Institutes of HealthBaltimoreMDUSA
| | - Kevin J. Pearson
- Graduate Center for Nutritional SciencesDepartment of Pharmacology and Nutritional SciencesUniversity of KentuckyLexingtonKYUSA
| | - Jose Manuel Villalba
- Department of Cell Biology, Physiology and ImmunologyAgrifood Campus of International Excellence, ceiA3University of CórdobaCórdobaSpain
| | - Placido Navas
- Centro Andaluz de Biologia del Desarrollo, and CIBERERInstituto de Salud Carlos IIIUniversidad Pablo de Olavide‐CSICSevillaSpain
| | - Michel Bernier
- Translational Gerontology BranchNational Institute on AgingNational Institutes of HealthBaltimoreMDUSA
| | - Rafael de Cabo
- Translational Gerontology BranchNational Institute on AgingNational Institutes of HealthBaltimoreMDUSA
- Nutritional Interventions Group, Precision Nutrition and AgingInstitute IMDEA FoodMadridSpain
| |
Collapse
|
|
11
|
Ravasz D, Kacso G, Fodor V, Horvath K, Adam-Vizi V, Chinopoulos C. Reduction of 2-methoxy-1,4-naphtoquinone by mitochondrially-localized Nqo1 yielding NAD + supports substrate-level phosphorylation during respiratory inhibition. BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS 2018; 1859:909-924. [PMID: 29746824 DOI: 10.1016/j.bbabio.2018.05.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Revised: 04/26/2018] [Accepted: 05/03/2018] [Indexed: 01/07/2023]
Abstract
Provision of NAD+ for oxidative decarboxylation of alpha-ketoglutarate to succinyl-CoA by the ketoglutarate dehydrogenase complex (KGDHC) is critical for maintained operation of succinyl-CoA ligase yielding high-energy phosphates, a process known as mitochondrial substrate-level phosphorylation (mSLP). We have shown previously that when NADH oxidation by complex I is inhibited by rotenone or anoxia, mitochondrial diaphorases yield NAD+, provided that suitable quinones are present (Kiss G et al., FASEB J 2014, 28:1682). This allows for KGDHC reaction to proceed and as an extension of this, mSLP. NAD(P)H quinone oxidoreductase 1 (NQO1) is an enzyme exhibiting diaphorase activity. Here, by using Nqo1-/- and WT littermate mice we show that in rotenone-treated, isolated liver mitochondria 2-methoxy-1,4-naphtoquinone (MNQ) is preferentially reduced by matrix Nqo1 yielding NAD+ to KGDHC, supporting mSLP. This process was sensitive to inhibition by specific diaphorase inhibitors. Reduction of idebenone and its analogues MRQ-20 and MRQ-56, menadione, mitoquinone and duroquinone were unaffected by genetic disruption of the Nqo1 gene. The results allow for the conclusions that i) MNQ is a Nqo1-preferred substrate, and ii) in the presence of suitable quinones, mitochondrially-localized diaphorases other than Nqo1 support NADH oxidation when complex I is inhibited. Our work confirms that complex I bypass can occur by quinones reduced by intramitochondrial diaphorases oxidizing NADH, ultimately supporting mSLP. Finally, it may help to elucidate structure-activity relationships of redox-active quinones with diaphorase enzymes.
Collapse
Affiliation(s)
- Dora Ravasz
- Department of Medical Biochemistry, Semmelweis University, Budapest 1094, Hungary
| | - Gergely Kacso
- Department of Medical Biochemistry, Semmelweis University, Budapest 1094, Hungary
| | - Viktoria Fodor
- Department of Medical Biochemistry, Semmelweis University, Budapest 1094, Hungary
| | - Kata Horvath
- Department of Medical Biochemistry, Semmelweis University, Budapest 1094, Hungary
| | - Vera Adam-Vizi
- Department of Medical Biochemistry, Semmelweis University, Budapest 1094, Hungary
| | - Christos Chinopoulos
- Department of Medical Biochemistry, Semmelweis University, Budapest 1094, Hungary.
| |
Collapse
|
|
12
|
Shi Q, Fijten RR, Spina D, Riffo Vasquez Y, Arlt VM, Godschalk RW, Van Schooten FJ. Altered gene expression profiles in the lungs of benzo[a]pyrene-exposed mice in the presence of lipopolysaccharide-induced pulmonary inflammation. Toxicol Appl Pharmacol 2017; 336:8-19. [PMID: 28987381 PMCID: PMC5703654 DOI: 10.1016/j.taap.2017.09.023] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Revised: 09/22/2017] [Accepted: 09/29/2017] [Indexed: 12/13/2022]
Abstract
Patients with inflammatory lung diseases are often additionally exposed to polycyclic aromatic hydrocarbons like B[a]P and B[a]P-induced alterations in gene expression in these patients may contribute to the development of lung cancer. Mice were intra-nasally treated with lipopolysaccharide (LPS, 20μg/mouse) to induce pulmonary inflammation and subsequently exposed to B[a]P (0.5mg/mouse) by intratracheal instillation. Gene expression changes were analyzed in mouse lungs by RNA microarrays. Analysis of genes that are known to be involved in the cellular response to B[a]P indicated that LPS significantly inhibited gene expression of various enzymes linked to B[a]P metabolism, which was confirmed by phenotypic analyses of enzyme activity. Ultimately, these changes resulted in higher levels of B[a]P-DNA adducts in the lungs of mice exposed to B[a]P with prior LPS treatment compared to the lungs of mice exposed to B[a]P alone. Using principle component analysis (PCA), we found that of all the genes that were significantly altered in their expression, those that were able to separate the different exposure conditions were predominantly related to immune-response. Moreover, an overall analysis of differentially expressed genes indicated that cell-cell adhesion and cell-cell communication was inhibited in lungs of mice that received both B[a]P and LPS. Our results indicate that pulmonary inflammation increased the genotoxicity of B[a]P via inhibition of both phase I and II metabolism. Therefore, inflammation could be a critical contributor to B[a]P-induced carcinogenesis in humans.
Collapse
Affiliation(s)
- Q Shi
- Department of Toxicology & Pharmacology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, PO Box 616, 6200, MD, Maastricht, The Netherlands
| | - R R Fijten
- Department of Toxicology & Pharmacology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, PO Box 616, 6200, MD, Maastricht, The Netherlands
| | - D Spina
- Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, 150 Stamford Street, London SE1 9NH, United Kingdom
| | - Y Riffo Vasquez
- Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, 150 Stamford Street, London SE1 9NH, United Kingdom
| | - V M Arlt
- Analytical and Environmental Sciences Division, MRC-PHE Centre for Environmental & Health, King's College London, 150 Stamford Street, London SE1 9NH, United Kingdom
| | - R W Godschalk
- Department of Toxicology & Pharmacology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, PO Box 616, 6200, MD, Maastricht, The Netherlands.
| | - F J Van Schooten
- Department of Toxicology & Pharmacology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, PO Box 616, 6200, MD, Maastricht, The Netherlands
| |
Collapse
|
|
13
|
Atiomo W, Shafiee MN, Chapman C, Metzler VM, Abouzeid J, Latif A, Chadwick A, Kitson S, Sivalingam VN, Stratford IJ, Rutland CS, Persson JL, Ødum N, Fuentes‐Utrilla P, Jeyapalan JN, Heery DM, Crosbie EJ, Mongan NP. Expression of NAD(P)H quinone dehydrogenase 1 (NQO1) is increased in the endometrium of women with endometrial cancer and women with polycystic ovary syndrome. Clin Endocrinol (Oxf) 2017; 87:557-565. [PMID: 28748640 PMCID: PMC5697576 DOI: 10.1111/cen.13436] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Revised: 05/11/2017] [Accepted: 07/24/2017] [Indexed: 01/28/2023]
Abstract
OBJECTIVE Women with a prior history of polycystic ovary syndrome (PCOS) have an increased risk of endometrial cancer (EC). AIM To investigate whether the endometrium of women with PCOS possesses gene expression changes similar to those found in EC. DESIGN AND METHODS Patients with EC, PCOS and control women unaffected by either PCOS or EC were recruited into a cross-sectional study at the Nottingham University Hospital, UK. For RNA sequencing, representative individual endometrial biopsies were obtained from women with EC, PCOS and a woman unaffected by PCOS or EC. Expression of a subset of differentially expressed genes identified by RNA sequencing, including NAD(P)H quinone dehydrogenase 1 (NQO1), was validated by quantitative reverse transcriptase PCR validation (n = 76) and in the cancer genome atlas UCEC (uterine corpus endometrioid carcinoma) RNA sequencing data set (n = 381). The expression of NQO1 was validated by immunohistochemistry in EC samples from a separate cohort (n = 91) comprised of consecutive patients who underwent hysterectomy at St Mary's Hospital, Manchester, between 2011 and 2013. A further 6 postmenopausal women with histologically normal endometrium who underwent hysterectomy for genital prolapse were also included. Informed consent and local ethics approval were obtained for the study. RESULTS We show for the first that NQO1 expression is significantly increased in the endometrium of women with PCOS and EC. Immunohistochemistry confirms significantly increased NQO1 protein expression in EC relative to nonmalignant endometrial tissue (P < .0001). CONCLUSIONS The results obtained here support a previously unrecognized molecular link between PCOS and EC involving NQO1.
Collapse
Affiliation(s)
- William Atiomo
- Faculty of Medicine and Health SciencesDivision of Obstetrics and Gynaecology and Child HealthSchool of MedicineQueen's Medical CentreNottingham University HospitalNottinghamUK
| | - Mohamad Nasir Shafiee
- Faculty of Medicine and Health SciencesDivision of Obstetrics and Gynaecology and Child HealthSchool of MedicineQueen's Medical CentreNottingham University HospitalNottinghamUK
- Faculty of MedicineDepartment Obstetrics and GynaecologyUKM Medical CentreCherasKuala LumpurMalaysia
| | - Caroline Chapman
- Faculty of Medicine and Health SciencesDivision of Obstetrics and Gynaecology and Child HealthSchool of MedicineQueen's Medical CentreNottingham University HospitalNottinghamUK
| | - Veronika M. Metzler
- Faculty of Medicine and Health SciencesSchool of Veterinary Medicine and ScienceUniversity of NottinghamNottinghamUK
| | - Jad Abouzeid
- Faculty of Medicine and Health SciencesSchool of Veterinary Medicine and ScienceUniversity of NottinghamNottinghamUK
| | - Ayşe Latif
- Faculty of Biology, Medicine and HealthDivision of Pharmacy and OptometrySchool of Health SciencesUniversity of ManchesterManchesterUK
| | - Amy Chadwick
- Faculty of BiologyDivision of Molecular & Clinical Cancer SciencesMedicine and HealthUniversity of ManchesterManchesterUK
| | - Sarah Kitson
- Faculty of BiologyDivision of Molecular & Clinical Cancer SciencesMedicine and HealthUniversity of ManchesterManchesterUK
- Department of Obstetrics and GynaecologyCentral Manchester University Hospitals NHS Foundation TrustManchester Academic Health Science CentreManchesterUK
- Manchester School of PharmacyUniversity of ManchesterManchesterUK
| | - Vanitha N. Sivalingam
- Faculty of BiologyDivision of Molecular & Clinical Cancer SciencesMedicine and HealthUniversity of ManchesterManchesterUK
- Department of Obstetrics and GynaecologyCentral Manchester University Hospitals NHS Foundation TrustManchester Academic Health Science CentreManchesterUK
- Manchester School of PharmacyUniversity of ManchesterManchesterUK
| | - Ian J. Stratford
- Faculty of Biology, Medicine and HealthDivision of Pharmacy and OptometrySchool of Health SciencesUniversity of ManchesterManchesterUK
| | - Catrin S. Rutland
- Faculty of Medicine and Health SciencesSchool of Veterinary Medicine and ScienceUniversity of NottinghamNottinghamUK
| | - Jenny L. Persson
- Clinical Research CenterLund UniversityMalmöSweden
- Department of Molecular BologyUmeå UniversityUmeåSweden
| | - Niels Ødum
- Department of Immunology and MicrobiologyUniversity of CopenhagenKobenhavnDenmark
| | | | - Jennie N. Jeyapalan
- Faculty of Medicine and Health SciencesSchool of Veterinary Medicine and ScienceUniversity of NottinghamNottinghamUK
| | | | - Emma J. Crosbie
- Faculty of BiologyDivision of Molecular & Clinical Cancer SciencesMedicine and HealthUniversity of ManchesterManchesterUK
- Department of Obstetrics and GynaecologyCentral Manchester University Hospitals NHS Foundation TrustManchester Academic Health Science CentreManchesterUK
- Manchester School of PharmacyUniversity of ManchesterManchesterUK
| | - Nigel P. Mongan
- Faculty of Medicine and Health SciencesSchool of Veterinary Medicine and ScienceUniversity of NottinghamNottinghamUK
- Department of PharmacologyWeill Cornell MedicineNew YorkNYUSA
| |
Collapse
|
|
14
|
Ross D, Siegel D. Functions of NQO1 in Cellular Protection and CoQ 10 Metabolism and its Potential Role as a Redox Sensitive Molecular Switch. Front Physiol 2017; 8:595. [PMID: 28883796 PMCID: PMC5573868 DOI: 10.3389/fphys.2017.00595] [Citation(s) in RCA: 228] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2017] [Accepted: 08/02/2017] [Indexed: 01/25/2023] Open
Abstract
NQO1 is one of the two major quinone reductases in mammalian systems. It is highly inducible and plays multiple roles in cellular adaptation to stress. A prevalent polymorphic form of NQO1 results in an absence of NQO1 protein and activity so it is important to elucidate the specific cellular functions of NQO1. Established roles of NQO1 include its ability to prevent certain quinones from one electron redox cycling but its role in quinone detoxification is dependent on the redox stability of the hydroquinone generated by two-electron reduction. Other documented roles of NQO1 include its ability to function as a component of the plasma membrane redox system generating antioxidant forms of ubiquinone and vitamin E and at high levels, as a direct superoxide reductase. Emerging roles of NQO1 include its function as an efficient intracellular generator of NAD+ for enzymes including PARP and sirtuins which has gained particular attention with respect to metabolic syndrome. NQO1 interacts with a growing list of proteins, including intrinsically disordered proteins, protecting them from 20S proteasomal degradation. The interactions of NQO1 also extend to mRNA. Recent identification of NQO1 as a mRNA binding protein have been investigated in more detail using SERPIN1A1 (which encodes the serine protease inhibitor α-1-antitrypsin) as a target mRNA and indicate a role of NQO1 in control of translation of α-1-antitrypsin, an important modulator of COPD and obesity related metabolic syndrome. NQO1 undergoes structural changes and alterations in its ability to bind other proteins as a result of the cellular reduced/oxidized pyridine nucleotide ratio. This suggests NQO1 may act as a cellular redox switch potentially altering its interactions with other proteins and mRNA as a result of the prevailing redox environment.
Collapse
Affiliation(s)
- David Ross
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy, University of Colorado Anschutz Medical CampusAurora, CO, United States
| | - David Siegel
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy, University of Colorado Anschutz Medical CampusAurora, CO, United States
| |
Collapse
|
|
15
|
Montes de Oca MK, Pearlman RL, McClees SF, Strickland R, Afaq F. Phytochemicals for the Prevention of Photocarcinogenesis. Photochem Photobiol 2017; 93:956-974. [PMID: 28063168 DOI: 10.1111/php.12711] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Accepted: 11/03/2016] [Indexed: 12/13/2022]
Abstract
Ultraviolet (UV) exposure has an array of damaging effects and is the main cause of skin cancer in humans. Nonmelanoma skin cancer (NMSC), including basal cell carcinoma and squamous cell carcinoma, is the most common type of cancer. Incidence of NMSC has increased due to greater UV radiation, increased life expectancy and other changes in lifestyle; the annual cost of skin cancer treatment in the United States has increased concurrently to around eight billion dollars. Because of these trends, novel approaches to skin cancer prevention have become an important area of research to decrease skin cancer morbidity and defray the costs associated with treatment. Chemoprevention aims to prevent or delay the development of skin cancer through the use of phytochemicals. Use of phytochemicals as chemopreventive agents has gained attention due to their low toxicity and anticarcinogenic properties. Phytochemicals also exhibit antioxidant, anti-inflammatory and antiproliferative effects which support their use as chemopreventive agents, particularly for skin cancer. Preclinical and human studies have shown that phytochemicals decrease UV-induced skin damage and photocarcinogenesis. In this review article, we discuss the selected phytochemicals that may prevent or delay UV-induced carcinogenesis and highlight their potential use for skin protection.
Collapse
Affiliation(s)
| | - Ross L Pearlman
- Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL
| | - Sarah F McClees
- Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL
| | - Rebecca Strickland
- Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL
| | - Farrukh Afaq
- Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL.,Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL
| |
Collapse
|
|
16
|
Kurfurstova D, Bartkova J, Vrtel R, Mickova A, Burdova A, Majera D, Mistrik M, Kral M, Santer FR, Bouchal J, Bartek J. DNA damage signalling barrier, oxidative stress and treatment-relevant DNA repair factor alterations during progression of human prostate cancer. Mol Oncol 2016; 10:879-94. [PMID: 26987799 DOI: 10.1016/j.molonc.2016.02.005] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Revised: 02/23/2016] [Accepted: 02/24/2016] [Indexed: 01/08/2023] Open
Abstract
The DNA damage checkpoints provide an anti-cancer barrier in diverse tumour types, however this concept has remained unexplored in prostate cancer (CaP). Furthermore, targeting DNA repair defects by PARP1 inhibitors (PARPi) as a cancer treatment strategy is emerging yet requires suitable predictive biomarkers. To address these issues, we performed immunohistochemical analysis of multiple markers of DNA damage signalling, oxidative stress, DNA repair and cell cycle control pathways during progression of human prostate disease from benign hyperplasia, through intraepithelial neoplasia to CaP, complemented by genetic analyses of TMPRSS2-ERG rearrangement and NQO1, an anti-oxidant factor and p53 protector. The DNA damage checkpoint barrier (γH2AX, pATM, p53) mechanism was activated during CaP tumorigenesis, albeit less and with delayed culmination compared to other cancers, possibly reflecting lower replication stress (slow proliferation despite cases of Rb loss and cyclin D1 overexpression) and progressive loss of ATM activator NKX3.1. Oxidative stress (8-oxoguanine lesions) and NQO1 increased during disease progression. NQO1 genotypes of 390 men did not indicate predisposition to CaP, yet loss of NQO1 in CaP suggested potential progression-opposing tumour suppressor role. TMPRSS2-ERG rearrangement and PTEN loss, events sensitizing to PARPi, occurred frequently along with heterogeneous loss of DNA repair factors 53BP1, JMJD1C and Rev7 (all studied here for the first time in CaP) whose defects may cause resistance to PARPi. Overall, our results reveal an unorthodox DNA damage checkpoint barrier scenario in CaP tumorigenesis, and provide novel insights into oxidative stress and DNA repair, with implications for biomarker guidance of future targeted therapy of CaP.
Collapse
Affiliation(s)
- Daniela Kurfurstova
- Department of Clinical and Molecular Pathology, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
| | - Jirina Bartkova
- Danish Cancer Society Research Center, Copenhagen, Denmark; Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
| | - Radek Vrtel
- Department of Medical Genetics, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic; Laboratory of Genome Integrity, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
| | - Alena Mickova
- Department of Clinical and Molecular Pathology, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
| | - Alena Burdova
- Department of Clinical and Molecular Pathology, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
| | - Dusana Majera
- Laboratory of Genome Integrity, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
| | - Martin Mistrik
- Laboratory of Genome Integrity, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
| | - Milan Kral
- Department of Urology, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic
| | - Frederic R Santer
- Division of Experimental Urology, Department of Urology, Medical University of Innsbruck, Austria
| | - Jan Bouchal
- Department of Clinical and Molecular Pathology, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.
| | - Jiri Bartek
- Danish Cancer Society Research Center, Copenhagen, Denmark; Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden; Laboratory of Genome Integrity, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.
| |
Collapse
|
|
17
|
Cui X, Li L, Yan G, Meng K, Lin Z, Nan Y, Jin G, Li C. High expression of NQO1 is associated with poor prognosis in serous ovarian carcinoma. BMC Cancer 2015; 15:244. [PMID: 25885439 PMCID: PMC4399114 DOI: 10.1186/s12885-015-1271-4] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Accepted: 03/26/2015] [Indexed: 12/02/2022] Open
Abstract
Background NAD(P)H:quinone oxidoreductase (NQO1) is a flavoprotein that catalyzes two-electron reduction and detoxification of quinones and its derivatives. NQO1 catalyzes reactions that have a protective effect against redox cycling, oxidative stress and neoplasia. High expression of NQO1 is associated with many solid tumors including those affecting the colon, breast and pancreas; however, its role in the progression of ovarian carcinoma is largely undefined. This study aimed to investigate the clinicopathological significance of high NQO1 expression in serous ovarian carcinoma. Methods NQO1 protein expression was assessed using immunohistochemical (IHC) staining in 160 patients with serous ovarian carcinoma, 62 patients with ovarian borderline tumors and 53 patients with benign ovarian tumors. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect NQO1 mRNA expression levels. The correlation between high NQO1 expression and clinicopathological features of ovarian carcinoma was evaluated by Chi-square and Fisher’s exact test. Overall survival (OS) rates of all of ovarian carcinoma patients were calculated using the Kaplan-Meier method, and univariate and multivariate analyses were performed using the Cox proportional hazards regression model. Results NQO1 protein expression in ovarian carcinoma cells was predominantly cytoplasmic. Strong, positive expression of NQO1 protein was observed in 63.8% (102/160) of ovarian carcinomas, which was significantly higher than in borderline serous tumors (32.3%, 20/62) or benign serous tumors (11.3%, 6/53). Importantly, the rate of strong, positive NQO1 expression in borderline serous tumors was also higher than in benign serous tumors. High expression of NQO1 protein was closely associated with higher histological grade, advanced clinical stage and lower OS rates in ovarian carcinomas. Moreover, multivariate analysis indicated that NQO1 was a significant independent prognostic factor, in addition to clinical stage, in patients with ovarian carcinoma. Conclusions NQO1 is frequently upregulated in ovarian carcinoma. High expressin of NQO1 protein may be an effective biomarker for poor prognostic evaluation of patients with serous ovarian carcinomas.
Collapse
Affiliation(s)
- Xuelian Cui
- Department of Pathology, Yanbian University Medical College, Yanji, 133002, China. .,Cancer Research Center, Yanbian University, Yanji, 133002, China.
| | - Lianhua Li
- Department of Gynecology & Obstetrics, Yanbian University Hospital, Yanji, 133000, China.
| | - Guanghai Yan
- Cancer Research Center, Yanbian University, Yanji, 133002, China.
| | - Kai Meng
- Cancer Research Center, Yanbian University, Yanji, 133002, China.
| | - Zhenhua Lin
- Department of Pathology, Yanbian University Medical College, Yanji, 133002, China. .,Cancer Research Center, Yanbian University, Yanji, 133002, China.
| | - Yunze Nan
- Department of Gynecology & Obstetrics, Yanbian University Hospital, Yanji, 133000, China.
| | - Guang Jin
- Department of Pathology, Yanbian University Medical College, Yanji, 133002, China.
| | - Chunyu Li
- Cancer Research Center, Yanbian University, Yanji, 133002, China.
| |
Collapse
|
|
18
|
Retraction: NRH:Quinone Oxidoreductase 2 and NAD(P)H:Quinone Oxidoreductase 1 Protect Tumor Suppressor p53 against 20S Proteasomal Degradation Leading to Stabilization and Activation of p53. Cancer Res 2015; 75:615. [DOI: 10.1158/0008-5472.can-14-3458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
|
|
19
|
Lee H, Oh ET, Choi BH, Park MT, Lee JK, Lee JS, Park HJ. NQO1-induced activation of AMPK contributes to cancer cell death by oxygen-glucose deprivation. Sci Rep 2015; 5:7769. [PMID: 25586669 PMCID: PMC4293602 DOI: 10.1038/srep07769] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2014] [Accepted: 12/17/2014] [Indexed: 11/26/2022] Open
Abstract
Oxygen and glucose deprivation (OGD) due to insufficient blood circulation can decrease cancer cell survival and proliferation in solid tumors. OGD increases the intracellular [AMP]/[ATP] ratio, thereby activating the AMPK. In this study, we have investigated the involvement of NQO1 in OGD-mediated AMPK activation and cancer cell death. We found that OGD activates AMPK in an NQO1-dependent manner, suppressing the mTOR/S6K/4E-BP1 pathway, which is known to control cell survival. Thus, the depletion of NQO1 prevents AMPK-induced cancer cell death in OGD. When we blocked OGD-induced Ca2+/CaMKII signaling, the NQO1-induced activation of AMPK was attenuated. In addition, when we blocked the RyR signaling, the accumulation of intracellular Ca2+ and subsequent activation of CaMKII/AMPK signaling was decreased in NQO1-expressing cells under OGD. Finally, siRNA-mediated knockdown of CD38 abrogated the OGD-induced activation of Ca2+/CaMKII/AMPK signaling. Taken together, we conclude that NQO1 plays a key role in the AMPK-induced cancer cell death in OGD through the CD38/cADPR/RyR/Ca2+/CaMKII signaling pathway.
Collapse
Affiliation(s)
- Hyemi Lee
- Department of Microbiology, Inha Research Institute for Medical Sciences, College of Medicine, Inha University, Incheon, Korea
| | - Eun-Taex Oh
- 1] Department of Microbiology, Inha Research Institute for Medical Sciences, College of Medicine, Inha University, Incheon, Korea [2] Hypoxia-related Disease Research Center, College of Medicine, Inha University, Incheon, Korea
| | - Bo-Hwa Choi
- 1] Department of Microbiology, Inha Research Institute for Medical Sciences, College of Medicine, Inha University, Incheon, Korea [2] Pohang Center for Evaluation of Biomaterials, Pohang Technopark, Pohang, Gyeongbuk, Korea
| | - Moon-Taek Park
- 1] Department of Microbiology, Inha Research Institute for Medical Sciences, College of Medicine, Inha University, Incheon, Korea [2] Research Center, Dongnam Institute of Radiological &Medical Sciences (DIRAMS), Busan, Korea
| | - Ja-Kyeong Lee
- 1] Hypoxia-related Disease Research Center, College of Medicine, Inha University, Incheon, Korea [2] Department of Anatomy, College of Medicine, Inha University, Incheon, Korea
| | - Jae-Seon Lee
- 1] Hypoxia-related Disease Research Center, College of Medicine, Inha University, Incheon, Korea [2] Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, Korea
| | - Heon Joo Park
- 1] Department of Microbiology, Inha Research Institute for Medical Sciences, College of Medicine, Inha University, Incheon, Korea [2] Hypoxia-related Disease Research Center, College of Medicine, Inha University, Incheon, Korea
| |
Collapse
|
|
20
|
Hu WG, Hu JJ, Cai W, Zheng MH, Zang L, Wang ZT, Zhu ZG. The NAD(P)H: quinine oxidoreductase 1 (NQO1) gene 609 C>T polymorphism is associated with gastric cancer risk: evidence from a case-control study and a meta-analysis. Asian Pac J Cancer Prev 2014; 15:2363-7. [PMID: 24716985 DOI: 10.7314/apjcp.2014.15.5.2363] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
UNLABELLED The association between the NAD(P)H quinone oxidoreductase 1 (NQO1) gene C609T polymorphism (rs1800566) and gastric cancer has been widely evaluated, but a definitive answer is so far lacking. We first conducted a case-control study to assess this association in a large Han Chinese population, and then performed a meta-analysis to further address this issue. Although our case-control association study indicated no significant difference in the genotype and allele distributions of C609T polymorphism between gastric cancer patients and controls, in the meta analysis involving 4,000 subjects, comparison of alleles 609T and 609C indicated a significantly increased risk (46%) for gastric cancer (95% confidence interval (95%CI) for odds ratio (OR)=1.20- 1.79) in individuals with the T allele. The tendency was similar to the homozygote (OR=1.81, 95%CI: 1.16-2.84), dominant models (OR=1.41, 95%CI: 1.12-1.79), as well as recessive model (OR=1.58, 95%CI: 1.06-2.35). Stratified analysis by study design demonstrated stronger associations in population-based than in hospital-based studies. And ethnicity-based analysis demonstrated a significant association in Asians. We conclude that the NQO1 gene C609T polymorphism increases the risk for gastric cancer, especially in Asian populations.
Collapse
Affiliation(s)
- Wei-Guo Hu
- Department of General Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China E-mail :
| | | | | | | | | | | | | |
Collapse
|
|
21
|
Targeting Nrf2-Keap1 signaling for chemoprevention of skin carcinogenesis with bioactive phytochemicals. Toxicol Lett 2014; 229:73-84. [DOI: 10.1016/j.toxlet.2014.05.018] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2014] [Revised: 05/18/2014] [Accepted: 05/20/2014] [Indexed: 01/09/2023]
|
|
22
|
Lee J, Kim KS, Lee MH, Kim YS, Lee MH, Lee SE, Kim YK, Ryu MJ, Kim SJ, Choi MJ, Jo YS. NAD(P)H: quinone oxidoreductase 1 and NRH:quinone oxidoreductase 2 polymorphisms in papillary thyroid microcarcinoma: correlation with phenotype. Yonsei Med J 2013; 54:1158-67. [PMID: 23918565 PMCID: PMC3743184 DOI: 10.3349/ymj.2013.54.5.1158] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
PURPOSE NAD(P)H:Quinone Oxidoreductase 1 (NQO1) C609T missense variant (NQO1*2) and 29 basepair (bp)-insertion/deletion (I29/D) polymorphism of the NRH:Quinone Oxidoreductase 2 (NQO2) gene promoter have been proposed as predictive and prognostic factors for cancer development and progression. The purpose of this study is to investigate the relationship between NQO1/NQO2 genotype and clinico-pathological features of papillary thyroid microcarcinoma (PTMC). MATERIALS AND METHODS Genomic DNA was isolated from 243 patients; and clinical data were retrospectively analyzed. NQO1*2 and tri-allelic polymorphism of NQO2 were investigated by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. RESULTS PTMC with NQO1*2 frequently exhibited extra-thyroidal extension as compared to PTMC with wild-type NQO1 (p=0.039). There was a significant relationship between I29/I29 homozygosity of NQO2 and lymph node metastasis (p=0.042). Multivariate analysis showed that the I29/I29 genotype was associated with an increased risk of lymph node metastasis (OR, 2.24; 95% CI, 1.10-4.56; p=0.026). CONCLUSION NQO1*2 and I29 allele of the NQO2 are associated with aggressive clinical phenotypes of PTMC, and the I29 allele represents a putative prognostic marker for PTMC.
Collapse
Affiliation(s)
- Junguee Lee
- Department of Pathology, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Daejeon, Korea
| | - Koon Soon Kim
- Research Center for Endocrine and Metabolic Diseases, Chungnam National University Hospital, Daejeon, Korea
| | - Min Ho Lee
- College of Biological Sciences and Biotechnology, Department of Bioscience, Chungnam National University, Daejeon, Korea
| | - Yeon Soo Kim
- Cheong Shim International Academy, Gapyeong, Korea
| | - Min Hee Lee
- Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Korea
| | - Seong Eun Lee
- Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Korea
| | - Yong Kyung Kim
- Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Korea
| | - Min Jeong Ryu
- Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Korea
| | - Soung Jung Kim
- Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Korea
| | - Min Jeong Choi
- Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Korea
| | - Young Suk Jo
- Research Center for Endocrine and Metabolic Diseases, Chungnam National University Hospital, Daejeon, Korea
| |
Collapse
|
|
23
|
Hayes CS, DeFeo-Mattox K, Woster PM, Gilmour SK. Elevated ornithine decarboxylase activity promotes skin tumorigenesis by stimulating the recruitment of bulge stem cells but not via toxic polyamine catabolic metabolites. Amino Acids 2013; 46:543-52. [PMID: 23884694 DOI: 10.1007/s00726-013-1559-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2013] [Accepted: 07/03/2013] [Indexed: 12/17/2022]
Abstract
Elevated expression of ornithine decarboxylase (ODC), the regulatory enzyme in polyamine biosynthesis, targeted to the epidermis is sufficient to promote skin tumor development following a single subthreshold dose of dimethylbenz(a)anthracene (DMBA). Since skin tumor promotion involves recruitment of hair follicle bulge stem cells harboring genetic lesions, we assessed the effect of increased epidermal ODC on recruitment of bulge stem cells in ODC-ER transgenic mice in which ODC activity is induced de novo in adult skin with 4-hydroxytamoxifen (4OHT). Bromodeoxyuridine-pulse labeling and use of K15.CrePR1;R26R;ODC-ER triple transgenic mice demonstrated that induction of ODC activity is sufficient to recruit bulge stem cells in quiescent skin. Because increased ODC activity not only stimulates proliferation but also increases reactive oxygen species (ROS) generation via subsequent induction of polyamine catabolic oxidases, we used an inhibitor of polyamine catabolic oxidase activity, MDL72527, to investigate whether ROS generation by polyamine catabolic oxidases contributes to skin tumorigenesis in DMBA-initiated ODC-ER transgenic skin. Newborn ODC-ER transgenic mice and their normal littermates were initiated with a single topical dose of DMBA. To assess tumor development originating from dormant bulge stem cells that possess DMBA-initiated mutations, epidermal ODC activity was induced in ODC-ER mice with 4OHT 5 weeks after DMBA initiation followed by MDL72527 treatment. MDL72527 treatment resulted in a shorter tumor latency time, increased tumor burden, increased conversion to carcinomas, and lower tumor levels of p53. Thus, elevated epidermal ODC activity promotes tumorigenesis by stimulating the recruitment of bulge stem cells but not via ROS generation by polyamine catabolic oxidases.
Collapse
Affiliation(s)
- Candace S Hayes
- Lankenau Institute for Medical Research, 100 Lancaster Avenue, Wynnewood, PA, 19096, USA
| | | | | | | |
Collapse
|
|
24
|
Singh N, Promkan M, Liu G, Varani J, Chakrabarty S. Role of calcium sensing receptor (CaSR) in tumorigenesis. Best Pract Res Clin Endocrinol Metab 2013; 27:455-63. [PMID: 23856272 DOI: 10.1016/j.beem.2013.04.001] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
The extracellular Ca(2+)-sensing receptor (CaSR) is a robust promoter of differentiation in colonic epithelial cells and functions as a tumor suppressor in colon cancer. CaSR mediates its biologic effects through diverse mechanisms. Loss of CaSR expression activates a myriad of stem cell-like molecular features that drive and sustain the malignant and drug-resistant phenotypes of colon cancer. This CaSR-null phenotype, however, is not irreversible and induction of CaSR expression in CaSR-null cells promotes cell death mechanisms and restores drug sensitivity. The CaSR also functions as a tumor suppressor in breast cancer and promotes cellular sensitivity to cytotoxic drugs. BRCA1 and CaSR functions intersect in breast cancer cells, and CaSR activation can rescue breast cancer cells from the deleterious effect of BRCA1 mutations.
Collapse
Affiliation(s)
- Navneet Singh
- Southern Illinois University School of Medicine, Department of Medical Microbiology, Immunology and Cell Biology and Simmons Cancer Institute, Springfield, IL, USA.
| | | | | | | | | |
Collapse
|
|
25
|
Morrissy S, Strom J, Purdom-Dickinson S, Chen QM. NAD(P)H:quinone oxidoreductase 1 is induced by progesterone in cardiomyocytes. Cardiovasc Toxicol 2013; 12:108-14. [PMID: 21947872 DOI: 10.1007/s12012-011-9144-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
NAD(P)H: quinone oxidoreductase 1 (NQO1) is a ubiquitous flavoenzyme that catalyzes two-electron reduction of various quinones by utilizing NAD(P)H as an electron donor. Our previous study found that progesterone (PG) can protect cardiomyocytes from apoptosis induced by doxorubicin (Dox). Microarray analyses of genes induced by PG had led to the discovery of induction of NQO1 mRNA. We report here that PG induces NQO1 protein and its activity in a dose-dependent manner. Whereas NQO1 is well known as a target gene of Nrf2 transcription factor due to the presence of antioxidant response element (ARE) in the promoter, PG did not activate the ARE, suggesting Nrf2-independent induction of NQO1. To address the role of NQO1 induction in PG-induced cytoprotection, we tested the effect of NQO1 inducer β-naphthoflavone and inhibitor dicoumarol. Induction of NQO1 by β-naphthoflavone decreased Dox-induced apoptosis and potentiated the protective effect of PG as measured by caspase-3 activity. PG-induced NQO1 activity was inhibited with dicoumarol, which did not affect PG-induced cytoprotection. Dicoumarol treatment alone potentiated Dox-induced caspase-3 activity. These data suggest that while NQO1 plays a role in PG-induced cytoprotection, there are additional components contributing to PG-induced cytoprotection.
Collapse
Affiliation(s)
- Stephen Morrissy
- Department of Pharmacology, College of Medicine, University of Arizona, 1501 N. Campbell Ave, Tucson, AZ 85724, USA
| | | | | | | |
Collapse
|
|
26
|
Guo ZJ, Feng CL. The NQO1 rs1800566 Polymorphism and Risk of Bladder Cancer: Evidence from 6,169 Subjects. Asian Pac J Cancer Prev 2012; 13:6343-8. [DOI: 10.7314/apjcp.2012.13.12.6343] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
|
|
27
|
Umar M, Upadhyay R, Kumar S, Ghoshal UC, Mittal B. Null association of NQO1 609C>T and NQO2 -3423G>A polymorphisms with susceptibility and prognosis of Esophageal cancer in north Indian population and meta-analysis. Cancer Epidemiol 2012; 36:e373-e379. [PMID: 22770696 DOI: 10.1016/j.canep.2012.06.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2012] [Revised: 06/10/2012] [Accepted: 06/13/2012] [Indexed: 12/15/2022]
Abstract
INTRODUCTION NAD(P)H:quinone oxidoreductase 1 (NQO1) and NRH:quinone oxidoreductase 2 (NQO2), involved in detoxification of environmental carcinogens and activation of chemotherapeutic agents, are supposed to play critical role in carcinogenesis. So, we aimed to investigate the association of NQO1 609C>T and NQO2 -3423G>A polymorphisms with susceptibility and prognosis of Esophageal cancer (EC) in north Indian population. We also performed Meta analysis of published literatures on NQO1 609C>T polymorphism to systematically evaluate its association with EC. METHODS We genotyped NQO1 609C>T and NQO2 -3423G>A polymorphisms in 200 incident EC cases (including 150 follow-up cases) and 200 controls using PCR RFLP based methods. Binary logistic regression was applied for risk estimation, while Kaplan Meier and Cox regression tests were applied for survival analysis. All Meta analysis tests were performed using MIX 2.0 software. RESULTS The present study did not find any significant association of NQO1 609C>T and NQO2 -3423G>A polymorphisms with susceptibility to EC or its clinical phenotypes (histopathology, tumor location or lymph node metastasis) or interactions with lifestyle risk factors (tobacco usage, smoking, alcohol habit and occupational exposures). Meta analysis of NQO1 polymorphism also indicated null association of the polymorphism with EC overall or with cancer cases stratified by tumor histopathology/ethnicity. Moreover, no prognostic implication of both polymorphisms was observed in EC. CONCLUSION NQO1 609C>T and NQO2 -3423G>A polymorphisms do not seem to play any significant role in susceptibility or prognosis of EC in north Indian population and results of Meta-analysis further reinforces null association of NQO1 609C>T polymorphism with EC susceptibility.
Collapse
Affiliation(s)
- Meenakshi Umar
- Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareilly Road, Lucknow 226014, India
| | | | | | | | | |
Collapse
|
|
28
|
Kumar R, Ansari KM, Chaudhari BP, Dhawan A, Dwivedi PD, Jain SK, Das M. Topical application of ochratoxin A causes DNA damage and tumor initiation in mouse skin. PLoS One 2012; 7:e47280. [PMID: 23071775 PMCID: PMC3468467 DOI: 10.1371/journal.pone.0047280] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2011] [Accepted: 09/13/2012] [Indexed: 11/19/2022] Open
Abstract
Skin cancer is one of the most common forms of cancer and 2-3 million new cases are being diagnosed globally each year. Along with UV rays, environmental pollutants/chemicals including mycotoxins, contaminants of various foods and feed stuffs, could be one of the aetiological factors of skin cancer. In the present study, we evaluated the DNA damaging potential and dermal carcinogenicity of a mycotoxin, ochratoxin A (OTA), with the rationale that dermal exposure to OTA in workers may occur during their involvement in pre and post harvest stages of agriculture. A single topical application of OTA (20-80 µg/mouse) resulted in significant DNA damage along with elevated γ-H2AX level in skin. Alteration in oxidative stress markers such as lipid peroxidation, protein carbonyl, glutathione content and antioxidant enzymes was observed in a dose (20-80 µg/mouse) and time-dependent (12-72 h) manner. The oxidative stress was further emphasized by the suppression of Nrf2 translocation to nucleus following a single topical application of OTA (80 µg/mouse) after 24 h. OTA (80 µg/mouse) application for 12-72 h caused significant enhancement in- (a) reactive oxygen species generation, (b) activation of ERK1/2, p38 and JNK MAPKs, (c) cell cycle arrest at G0/G1 phase (37-67%), (d) induction of apoptosis (2.0-11.0 fold), (e) expression of p53, p21/waf1, (f) Bax/Bcl-2 ratio, (g) cytochrome c level, (h) activities of caspase 9 (1.2-1.8 fold) and 3 (1.7-2.2 fold) as well as poly ADP ribose polymerase cleavage. In a two-stage mouse skin tumorigenesis protocol, it was observed that a single topical application of OTA (80 µg/mouse) followed by twice weekly application of 12-O-tetradecanoylphorbol-13-acetate for 24 week leads to tumor formation. These results suggest that OTA has skin tumor initiating property which may be related to oxidative stress, MAPKs signaling and DNA damage.
Collapse
Affiliation(s)
- Rahul Kumar
- Food, Drug and Chemical Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, Uttar Pradesh, India
- Department of Biotechnology, Faculty of Science, Jamia Hamdard (Hamdard University), New Delhi, India
| | - Kausar M. Ansari
- Food, Drug and Chemical Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, Uttar Pradesh, India
- * E-mail: (MD); (KMA)
| | - Bhushan P. Chaudhari
- Pathology Laboratory, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, Uttar Pradesh, India
| | - Alok Dhawan
- Nanotoxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, Uttar Pradesh, India
| | - Premendra D. Dwivedi
- Food, Drug and Chemical Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, Uttar Pradesh, India
| | - Swatantra K. Jain
- Department of Biotechnology, Faculty of Science, Jamia Hamdard (Hamdard University), New Delhi, India
| | - Mukul Das
- Food, Drug and Chemical Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Lucknow, Uttar Pradesh, India
- * E-mail: (MD); (KMA)
| |
Collapse
|
|
29
|
Zhang Y, Wang ZT, Zhong J. Meta-analysis demonstrates that the NAD(P)H: quinone oxidoreductase 1 (NQO1) gene 609 C>T polymorphism is associated with increased gastric cancer risk in Asians. GENETICS AND MOLECULAR RESEARCH 2012; 11:2328-37. [PMID: 22911602 DOI: 10.4238/2012.august.13.6] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
The association between the NAD(P)H: quinone oxidoreductase 1 (NQO1) gene C609T polymorphism and gastric cancer has been widely evaluated, yet with conflicting results. Data were available from seven study populations involving 2600 subjects. Overall, comparison of alleles 609T and 609C indicated a significantly increased risk (46%) for gastric cancer (95% confidence interval (95%CI) for odds ratio (OR) = 1.20-1.79) in individuals with the T allele. The tendency was increased in the homozygous comparison (609TT versus 609CC), with an OR = 2.04 (95%CI = 1.37-3.05). Stratified analysis by study design demonstrated stronger associations in population-based studies than in hospital-based studies, based on OR. Ethnicity-based analysis demonstrated a significant association in Asians but not in Caucasians. Additionally, in the subgroup analyses by the type of gastric cancer, a significantly increased risk was found with all genetic models in the gastric adenocarcinoma subgroup compared to the others. We conclude that the NQO1 gene C609T polymorphism increases the risk for gastric cancer, especially in Asian populations.
Collapse
Affiliation(s)
- Y Zhang
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | | | | |
Collapse
|
|
30
|
Krishnamurthy N, Hu Y, Siedlak S, Doughman YQ, Watanabe M, Montano MM. Induction of quinone reductase by tamoxifen or DPN protects against mammary tumorigenesis. FASEB J 2012; 26:3993-4002. [PMID: 22700872 DOI: 10.1096/fj.12-208330] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
We have previously shown that estrogen receptor β (ERβ)-mediated up-regulation of quinone reductase (QR) is involved in the protection against estrogen-induced mammary tumorigenesis. Our present study provides evidence that the ERβ agonist, 2,3-bis-(4-hydroxy-phenyl)-propionitrile (DPN), and the selective estrogen receptor modulator tamoxifen (Tam), inhibit estrogen-induced DNA damage and mammary tumorigenesis in the aromatase transgenic (Arom) mouse model. We also show that either DPN or Tam treatment increases QR levels and results in a decrease in ductal hyperplasia, proliferation, oxidative DNA damage (ODD), and an increase in apoptosis. To corroborate the role of QR, we provide additional evidence in triple transgenic MMTV/QR/Arom mice, wherein the QR expression is induced in the mammary glands via doxycycline, causing a decrease in ductal hyperplasia and ODD. Overall, we provide evidence that up-regulation of QR through induction by Tam or DPN can inhibit estrogen-induced ODD and mammary cell tumorigenesis, representing a novel mechanism of prevention against breast cancer. Thus, our data have important clinical implications in the management of breast cancer; our findings bring forth potentially new therapeutic strategies involving ERβ agonists.
Collapse
Affiliation(s)
- Nirmala Krishnamurthy
- Case Western Reserve University, School of Medicine, Department of Pharmacology, H. G.Wood Bldg. W305, 2109 Adelbert Rd., Cleveland, OH 44106, USA
| | | | | | | | | | | |
Collapse
|
|
31
|
Stress-induced NQO1 controls stability of C/EBPα against 20S proteasomal degradation to regulate p63 expression with implications in protection against chemical-induced skin cancer. Oncogene 2012; 31:4362-71. [PMID: 22249251 PMCID: PMC3538879 DOI: 10.1038/onc.2011.600] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Previously, we have shown a role of cytosolic NAD(P)H:quinone oxidoreductase 1 (NQO1) in stabilization of p63 against 20S proteasomal degradation resulting in thinning of epithelium and chemical-induced skin cancer [Oncogene (2011) 30,1098–1107]. Current studies demonstrate that NQO1 control of C/EBPα against20S proteasomal degradation also contributes to the up regulation of p63 expression and protection. Western and immunohistochemistry analysis revealed that disruption of NQO1 gene in mice and mouse keratinocytes led todegradation of C/EBPα and loss of p63 gene expression. p63 promoter mutagenesis, transfection and ChIP assays identified C/EBPα binding site between nucleotide position −185 to −174 that bound to C/EBPα and up regulated p63 gene expression. Coimmunoprecipitation and immunoblot analysis demonstrated that 20S proteasomes directly interacted and degraded C/EBPα. NQO1 direct interaction with C/EBPα led to stabilization of C/EBPα against 20S proteasomal degradation. NQO1 protection of C/EBPα required binding of NADH with NQO1. Exposure of skin and keratinocytes to chemical stress agent benzo(a)pyrene led to induction of NQO1 and stabilization of C/EBPα protein resulting in an increase in p63 RNA and protein in wild type but not in NQO1−/− mice. Collectively, the current data combined with previous suggest that stress-induction of NQO1 through both stabilization of C/EBPα and increase in p63 and direct stabilization of p63 controls keratinocyte differentiation leading to protection against chemical-induced skin carcinogenesis. The studies are significant since 2–4% human individuals are homozygous and 23% are heterozygous for NQO1P187S mutation and might be susceptible to stress-induced skin diseases.
Collapse
|
|
32
|
Kim HJ, Zheng M, Kim SK, Cho JJ, Shin CH, Joe Y, Chung HT. CO/HO-1 Induces NQO-1 Expression via Nrf2 Activation. Immune Netw 2011; 11:376-82. [PMID: 22346778 PMCID: PMC3275707 DOI: 10.4110/in.2011.11.6.376] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2011] [Revised: 10/21/2011] [Accepted: 11/07/2011] [Indexed: 12/15/2022] Open
Abstract
Background Carbon monoxide (CO) is a cytoprotective and homeostatic molecule with important signaling capabilities in physiological and pathophysiological situations. CO protects cells/tissues from damage by free radicals or oxidative stress. NAD(P)H:quinone oxidoreductase (NQO1) is a highly inducible enzyme that is regulated by the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway, which is central to efficient detoxification of reactive metabolites and reactive oxygen species (ROS). Methods We generated NQO1 promoter construct. HepG2 cells were treated with CO Releasing Molecules-2 (CORM-2) or CO gas and the gene expressions were measured by RT-PCR, immunoblot, and luciferase assays. Results CO induced expression of NQO1 in human hepatocarcinoma cell lines by activation of Nrf2. Exposure of HepG2 cells to CO resulted in significant induction of NQO1 in dose- and time-dependent manners. Analysis of the NQO1 promoter indicated that an antioxidant responsible element (ARE)-containing region was critical for the CO-induced Nrf2-dependent increase of NQO1 gene expression in HepG2 cells. Conclusion Our results suggest that CO-induced Nrf2 increases the expression of NQO1 which is well known to detoxify reactive metabolites and ROS.
Collapse
Affiliation(s)
- Hyo Jeong Kim
- School of Biological Sciences, University of Ulsan, Ulsan 680-749, Korea
| | | | | | | | | | | | | |
Collapse
|
|
33
|
Tsai CW, Lin CY, Wang YJ. Carnosic acid induces the NAD(P)H: quinone oxidoreductase 1 expression in rat clone 9 cells through the p38/nuclear factor erythroid-2 related factor 2 pathway. J Nutr 2011; 141:2119-25. [PMID: 22031657 DOI: 10.3945/jn.111.146779] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
The anticarcinogenic effect of rosemary has been partly attributed to the modulation of the activity and expression of phase II detoxification enzymes. Here we compared the effects of phenolic diterpenes from rosemary on the expression of NAD(P)H: quinone oxidoreductase 1 (NQO1) in rat Clone 9 liver cells. Cells were treated with 1-20 μmol/L of carnosic acid (CA) or carnosol (CS) for 24 h. Both CA and CS dose dependently increased NQO1 enzyme activity and protein expression, and the induction potency of CA was stronger than that of CS. The increase in NQO1 enzyme activity in cells treated with 10 μmol/L CA and CS was 4.1- and 1.9-fold, respectively (P < 0.05). RT-PCR showed that CA and CS induced NQO1 mRNA in a dose-dependent manner. Furthermore, CA dose dependently induced transcription of nuclear factor erythroid-2 related factor 2 (Nrf2) and antioxidant response element (ARE)-luciferase reporter activity. Silencing of Nrf2 expression alleviated NQO1 protein expression and ARE-luciferase activity by CA. Moreover, the phosphorylation of p38 was mainly stimulated in the presence of CA. Pretreatment with SB203580 or silencing of p38 expression inhibited Nrf2 activation and NQO1 induction. These results suggest that the increased NQO1 expression by CA is likely related to the p38-Nrf2 pathway and help to clarify the possible molecular mechanism of action of rosemary phenolic compounds in drug metabolism and cancer prevention.
Collapse
Affiliation(s)
- Chia-Wen Tsai
- Department of Nutrition, China Medical University, Taichung 404, Taiwan.
| | | | | |
Collapse
|
|
34
|
Nolan KA, Dunstan MS, Caraher MC, Scott KA, Leys D, Stratford IJ. In silico screening reveals structurally diverse, nanomolar inhibitors of NQO2 that are functionally active in cells and can modulate NF-κB signaling. Mol Cancer Ther 2011; 11:194-203. [PMID: 22090421 DOI: 10.1158/1535-7163.mct-11-0543] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The National Cancer Institute chemical database has been screened using in silico docking to identify novel nanomolar inhibitors of NRH:quinone oxidoreductase 2 (NQO2). The inhibitors identified from the screen exhibit a diverse range of scaffolds and the structure of one of the inhibitors, NSC13000 cocrystalized with NQO2, has been solved. This has been used to aid the generation of a structure-activity relationship between the computationally derived binding affinity and experimentally measured enzyme inhibitory potency. Many of the compounds are functionally active as inhibitors of NQO2 in cells at nontoxic concentrations. To show this, advantage was taken of the NQO2-mediated toxicity of the chemotherapeutic drug CB1954. The toxicity of this drug is substantially reduced when the function of NQO2 is inhibited, and many of the compounds achieve this in cells at nanomolar concentrations. The NQO2 inhibitors also attenuated TNFα-mediated, NF-кB-driven transcriptional activity. The link between NQO2 and the regulation of NF-кB was confirmed by using short interfering RNA to NQO2 and by the observation that NRH, the cofactor for NQO2 enzyme activity, could regulate NF-кB activity in an NQO2-dependent manner. NF-кB is a potential therapeutic target and this study reveals an underlying mechanism that may be usable for developing new anticancer drugs.
Collapse
Affiliation(s)
- Karen A Nolan
- School of Pharmacy and Pharmaceutical Sciences, University of Manchester and Manchester Cancer Research Centre, Manchester M13 9PT, United Kingdom
| | | | | | | | | | | |
Collapse
|
|
35
|
Wang Z, Hu J, Zhong J. Meta-analysis of the NAD(P)H: quinine oxidoreductase 1 gene 609 C>T polymorphism with esophageal cancer risk. DNA Cell Biol 2011; 31:560-7. [PMID: 22017531 DOI: 10.1089/dna.2011.1332] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Association between the NAD(P)H: quinine oxidoreductase 1 (NQO1) gene 609 C>T polymorphism and esophageal cancer (EC) has been widely evaluated; however, the results are often irreproducible. We thus aimed to comprehensively evaluate this association through a meta-analysis. Data were extracted from 10 study populations involving 1390 EC patients and 1812 controls, and were analyzed using STATA software. Random-effects model was applied irrespective of between-study heterogeneity, which was assessed by the inconsistency index (I(2)) statistic. Publication bias was weighted by the funnel plot and Egger's test. Genotype distributions of the NQO1 gene 609 C>T polymorphism met Hardy-Weinberg equilibrium in controls for all studies. Allelic comparison indicated that NQO1 609 T allele conferred an increased risk (odds ratio [OR]=1.23; 95% confidence interval [CI]: 1.02-1.49; p=0.035), accompanying significant heterogeneity (I(2)=63.4%, p=0.003) and no publication bias (p(Egger)=0.391). This association was potentially enhanced in homozygous comparison (OR=1.58; 95% CI: 1.03-2.41; p=0.035; I(2)= 55.4%, p(heterogeneity)=0.017 and p(Egger)=0.461). Under dominant and recessive models, similar associations were obtained with an increased, although marginally significant risk. Subgroup analysis by ethnicity supported the risk profiles of the NQO1 gene 609 T allele and 609 TT genotype with EC in Eastern Asians, not in Europeans. Meta-regression analysis indicated that association between the NQO1 gene 609 C>T polymorphism and EC risk was significantly decreased with aging in case-patients (R(2)=-0.57; p=0.042). We expand previous studies by showing that the NQO1 gene 609 C>T polymorphism might contribute to EC occurrence, especially in Eastern Asians.
Collapse
Affiliation(s)
- Zhengting Wang
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | | | | |
Collapse
|
|
36
|
Gene expression signature analysis identifies vorinostat as a candidate therapy for gastric cancer. PLoS One 2011; 6:e24662. [PMID: 21931799 PMCID: PMC3170379 DOI: 10.1371/journal.pone.0024662] [Citation(s) in RCA: 88] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2011] [Accepted: 08/16/2011] [Indexed: 02/03/2023] Open
Abstract
BACKGROUND Gastric cancer continues to be one of the deadliest cancers in the world and therefore identification of new drugs targeting this type of cancer is thus of significant importance. The purpose of this study was to identify and validate a therapeutic agent which might improve the outcomes for gastric cancer patients in the future. METHODOLOGY/PRINCIPAL FINDINGS Using microarray technology, we generated a gene expression profile of human gastric cancer-specific genes from human gastric cancer tissue samples. We used this profile in the Broad Institute's Connectivity Map analysis to identify candidate therapeutic compounds for gastric cancer. We found the histone deacetylase inhibitor vorinostat as the lead compound and thus a potential therapeutic drug for gastric cancer. Vorinostat induced both apoptosis and autophagy in gastric cancer cell lines. Pharmacological and genetic inhibition of autophagy however, increased the therapeutic efficacy of vorinostat, indicating that a combination of vorinostat with autophagy inhibitors may therapeutically be more beneficial. Moreover, gene expression analysis of gastric cancer identified a collection of genes (ITGB5, TYMS, MYB, APOC1, CBX5, PLA2G2A, and KIF20A) whose expression was elevated in gastric tumor tissue and downregulated more than 2-fold by vorinostat treatment in gastric cancer cell lines. In contrast, SCGB2A1, TCN1, CFD, APLP1, and NQO1 manifested a reversed pattern. CONCLUSIONS/SIGNIFICANCE We showed that analysis of gene expression signature may represent an emerging approach to discover therapeutic agents for gastric cancer, such as vorinostat. The observation of altered gene expression after vorinostat treatment may provide the clue to identify the molecular mechanism of vorinostat and those patients likely to benefit from vorinostat treatment.
Collapse
|
|
37
|
Gao M, Li Y, Sun Y, Long J, Kong Y, Yang S, Wang Y. A common carcinogen benzo[a]pyrene causes p53 overexpression in mouse cervix via DNA damage. Mutat Res 2011; 724:69-75. [PMID: 21745588 DOI: 10.1016/j.mrgentox.2011.06.008] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2011] [Revised: 05/05/2011] [Accepted: 06/26/2011] [Indexed: 12/13/2022]
Abstract
Benzo[a]pyrene (BaP) is cytotoxic and/or genotoxic to lung, stomach and skin tissue in the body. However, the effect of BaP on cervical tissue remains unclear. The present study detected DNA damage and the expression of the p53 gene in BaP-induced cervical tissue in female mice. Animals were intraperitoneally injected and orally gavaged with BaP at the doses of 2.5, 5, and 10mg/kg twice a week for 14 weeks. The single-cell gel electrophoresis (SCGE) assay was used to detect the DNA damage. Immunohistochemistry (IHC) and in situ hybridization (ISH) were used to detect the expression of p53 protein and p53 mRNA, respectively. The results showed that BaP induced a significant and dose-dependent increase of the number of cells with DNA damaged and the tail length as well as Comet tail moment in cervical tissue. The expression level of p53 protein and mRNA was increased. The results demonstrate that BaP may show toxic effect on the cervix by increasing DNA damage and the expression of the p53 gene.
Collapse
Affiliation(s)
- Meili Gao
- Institute of Cancer Research, Department of Biological Science and Engineering, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, Xi'an Jiaotong University School of Life Science and Technology, Xi'an, Shaanxi 710049, China.
| | | | | | | | | | | | | |
Collapse
|
|
38
|
Anttila S, Raunio H, Hakkola J. Cytochrome P450-mediated pulmonary metabolism of carcinogens: regulation and cross-talk in lung carcinogenesis. Am J Respir Cell Mol Biol 2011; 44:583-90. [PMID: 21097654 DOI: 10.1165/rcmb.2010-0189rt] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2023] Open
Abstract
Lung cancer is strongly associated with exogenous risk factors, in particular tobacco smoking and asbestos exposure. New research data are accumulating about the regulation of the metabolism of tobacco carcinogens and the metabolic response to oxidative stress. These data provide mechanistic details about why well known risk factors cause lung cancer. The purpose of this review is to evaluate the present knowledge of the role of cytochrome P450 (CYP) enzymes in the metabolism of tobacco carcinogens and associations with tobacco and asbestos carcinogenesis. Major emphasis is placed on human data and regulatory pathways involved in CYP regulation and lung carcinogenesis. The most exciting new research findings concern cross-talk of the CYP-regulating aryl hydrocarbon receptor with other transcription factors, such as nuclear factor-erythroid 2-related factor 2, involved in the regulation of xenobiotic metabolism and antioxidant enzymes. This cross-talk between transcription factors may provide mechanistic evidence for clinically relevant issues, such as differences in lung cancers between men and women and the synergism between tobacco and asbestos as lung carcinogens.
Collapse
Affiliation(s)
- Sisko Anttila
- Dept. of Pathology, HUSLAB and Helsinki University Hospital, Finland.
| | | | | |
Collapse
|
|
39
|
Ghosh S, Tan F, Yu T, Li Y, Adisa O, Mosunjac M, Ofori-Acquah SF. Global gene expression profiling of endothelium exposed to heme reveals an organ-specific induction of cytoprotective enzymes in sickle cell disease. PLoS One 2011; 6:e18399. [PMID: 21483798 PMCID: PMC3069101 DOI: 10.1371/journal.pone.0018399] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2010] [Accepted: 03/06/2011] [Indexed: 01/23/2023] Open
Abstract
BACKGROUND Sickle cell disease (SCD) is characterized by hemolysis, vaso-occlusion and ischemia reperfusion injury. These events cause endothelial dysfunction and vasculopathies in multiple systems. However, the lack of atherosclerotic lesions has led to the idea that there are adaptive mechanisms that protect the endothelium from major vascular insults in SCD patients. The molecular bases for this phenomenon are poorly defined. This study was designed to identify the global profile of genes induced by heme in the endothelium, and assess expression of the heme-inducible cytoprotective enzymes in major organs impacted by SCD. METHODS AND FINDINGS Total RNA isolated from heme-treated endothelial monolayers was screened with the Affymetrix U133 Plus 2.0 chip, and the microarray data analyzed using multiple bioinformatics software. Hierarchical cluster analysis of significantly differentially expressed genes successfully segregated heme and vehicle-treated endothelium. Validation studies showed that the induction of cytoprotective enzymes by heme was influenced by the origin of endothelial cells, the duration of treatment, as well as the magnitude of induction of individual enzymes. In agreement with these heterogeneities, we found that induction of two major Nrf2-regulated cytoprotective enzymes, heme oxygenase-1 and NAD(P)H:quinone oxidoreductase-1 is organ-specific in two transgenic mouse models of SCD. This data was confirmed in the endothelium of post-mortem lung tissues of SCD patients. CONCLUSIONS Individual organ systems induce unique profiles of cytoprotective enzymes to neutralize heme in SCD. Understanding this heterogeneity may help to develop effective therapies to manage vasculopathies of individual systems.
Collapse
Affiliation(s)
- Samit Ghosh
- Aflac Cancer Center and Blood Disorders Service, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, United States of America
| | - Fang Tan
- Aflac Cancer Center and Blood Disorders Service, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, United States of America
| | - Tianwei Yu
- Department of Biostatics and Bioinformatics, Emory University School of Medicine, Atlanta, Georgia, United States of America
| | - Yuhua Li
- Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, United States of America
| | - Olufolake Adisa
- Aflac Cancer Center and Blood Disorders Service, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, United States of America
| | - Mario Mosunjac
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America
| | - Solomon F. Ofori-Acquah
- Aflac Cancer Center and Blood Disorders Service, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, United States of America
- Center for Endothelial Biology, Children's Healthcare of Atlanta, Atlanta, Georgia, United States of America
- * E-mail:
| |
Collapse
|
|
40
|
Ginsberg G, Guyton K, Johns D, Schimek J, Angle K, Sonawane B. Genetic polymorphism in metabolism and host defense enzymes: implications for human health risk assessment. Crit Rev Toxicol 2011; 40:575-619. [PMID: 20662711 DOI: 10.3109/10408441003742895] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Genetic polymorphisms in xenobiotic metabolizing enzymes can have profound influence on enzyme function, with implications for chemical clearance and internal dose. The effects of polymorphisms have been evaluated for certain therapeutic drugs but there has been relatively little investigation with environmental toxicants. Polymorphisms can also affect the function of host defense mechanisms and thus modify the pharmacodynamic response. This review and analysis explores the feasibility of using polymorphism data in human health risk assessment for four enzymes, two involved in conjugation (uridine diphosphoglucuronosyltransferases [UGTs], sulfotransferases [SULTs]), and two involved in detoxification (microsomal epoxide hydrolase [EPHX1], NADPH quinone oxidoreductase I [NQO1]). This set of evaluations complements our previous analyses with oxidative and conjugating enzymes. Of the numerous UGT and SULT enzymes, the greatest likelihood for polymorphism effect on conjugation function are for SULT1A1 (*2 polymorphism), UGT1A1 (*6, *7, *28 polymorphisms), UGT1A7 (*3 polymorphism), UGT2B15 (*2 polymorphism), and UGT2B17 (null polymorphism). The null polymorphism in NQO1 has the potential to impair host defense. These highlighted polymorphisms are of sufficient frequency to be prioritized for consideration in chemical risk assessments. In contrast, SNPs in EPHX1 are not sufficiently influential or defined for inclusion in risk models. The current analysis is an important first step in bringing the highlighted polymorphisms into a physiologically based pharmacokinetic (PBPK) modeling framework.
Collapse
Affiliation(s)
- Gary Ginsberg
- Connecticut Department of Public Health, Hartford, Connecticut 06106, USA.
| | | | | | | | | | | |
Collapse
|
|
41
|
Lindemer BJ, Bongard RD, Hoffmann R, Baumgardt S, Gonzalez FJ, Merker MP. Genetic evidence for NAD(P)H:quinone oxidoreductase 1-catalyzed quinone reduction on passage through the mouse pulmonary circulation. Am J Physiol Lung Cell Mol Physiol 2011; 300:L773-80. [PMID: 21296895 DOI: 10.1152/ajplung.00394.2010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The quinones duroquinone (DQ) and coenzyme Q(1) (CoQ(1)) and quinone reductase inhibitors have been used to identify reductases involved in quinone reduction on passage through the pulmonary circulation. In perfused rat lung, NAD(P)H:quinone oxidoreductase 1 (NQO1) was identified as the predominant DQ reductase and NQO1 and mitochondrial complex I as the CoQ(1) reductases. Since inhibitors have nonspecific effects, the goal was to use Nqo1-null (NQO1(-)/(-)) mice to evaluate DQ as an NQO1 probe in the lung. Lung homogenate cytosol NQO1 activities were 97 ± 11, 54 ± 6, and 5 ± 1 (SE) nmol dichlorophenolindophenol reduced·min(-1)·mg protein(-1) for NQO1(+/+), NQO1(+/-), and NQO1(-/-) lungs, respectively. Intact lung quinone reduction was evaluated by infusion of DQ (50 μM) or CoQ(1) (60 μM) into the pulmonary arterial inflow of the isolated perfused lung and measurement of pulmonary venous effluent hydroquinone (DQH(2) or CoQ(1)H(2)). DQH(2) efflux rates for NQO1(+/+), NQO1(+/-), and NQO1(-/-) lungs were 0.65 ± 0.08, 0.45 ± 0.04, and 0.13 ± 0.05 (SE) μmol·min(-1)·g dry lung(-1), respectively. DQ reduction in NQO1(+/+) lungs was inhibited by 90 ± 4% with dicumarol; there was no inhibition in NQO1(-/-) lungs. There was no significant difference in CoQ(1)H(2) efflux rates for NQO1(+/+) and NQO1(-/-) lungs. Differences in DQ reduction were not due to differences in lung dry weights, wet-to-dry weight ratios, perfusion pressures, perfused surface areas, or total DQ recoveries. The data provide genetic evidence implicating DQ as a specific NQO1 probe in the perfused rodent lung.
Collapse
Affiliation(s)
- Brian J Lindemer
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | | | | | | | | | | |
Collapse
|
|
42
|
Lee IS, Lim J, Gal J, Kang JC, Kim HJ, Kang BY, Choi HJ. Anti-inflammatory activity of xanthohumol involves heme oxygenase-1 induction via NRF2-ARE signaling in microglial BV2 cells. Neurochem Int 2011; 58:153-60. [DOI: 10.1016/j.neuint.2010.11.008] [Citation(s) in RCA: 133] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2010] [Revised: 10/25/2010] [Accepted: 11/10/2010] [Indexed: 01/07/2023]
|
|
43
|
Scott KA, Barnes J, Whitehead RC, Stratford IJ, Nolan KA. Inhibitors of NQO1: identification of compounds more potent than dicoumarol without associated off-target effects. Biochem Pharmacol 2011; 81:355-63. [PMID: 20970406 DOI: 10.1016/j.bcp.2010.10.011] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2010] [Revised: 10/13/2010] [Accepted: 10/14/2010] [Indexed: 01/20/2023]
Abstract
The enzyme NAD(P)H quinone oxidoreductase (NQO1) can function both as a detoxifying enzyme as well as chaperone protein. The latter property has been extensively characterized by the use of dicoumarol which inhibits the chaperone properties of NQO1 in cells. However, the use of this compound is compromised by its multiple "off-target" effects. Coumarin-based compounds that are more potent than dicoumarol as inhibitors of NQO1 in cells have been identified (Nolan et al., Biochem Pharmacol 2010;80:977-81). The purpose of the work reported here is to evaluate the off-target effects of these compounds when compared to dicoumarol. A range of these substituted coumarins are identified that are significantly less toxic than dicoumarol in a panel of nine cell lines. Further a number of the compounds generate much less intracellular superoxide, and many of them also show a reduced ability to induce apoptosis when compared to dicoumarol. None of these effects correlate with the ability of the compounds to inhibit the enzymatic activity of NQO1 in cells. In conclusion, potent inhibitors of NQO1 have been identified that will be more pharmacologically useful than dicoumarol for probing the function of NQO1 in cells and tissues.
Collapse
Affiliation(s)
- Katherine Ann Scott
- School of Pharmacy and Pharmaceutical Sciences, University of Manchester and Manchester Cancer Research Centre, Oxford Road, Manchester, UK
| | | | | | | | | |
Collapse
|
|
44
|
Gao M, Long J, Li Y, Shah W, Fu L, Liu J, Wang Y. Mitochondrial decay is involved in BaP-induced cervical damage. Free Radic Biol Med 2010; 49:1735-45. [PMID: 20851761 DOI: 10.1016/j.freeradbiomed.2010.09.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2010] [Revised: 08/24/2010] [Accepted: 09/03/2010] [Indexed: 12/13/2022]
Abstract
Benzo[a]pyrene (BaP) is a polycyclic aromatic hydrocarbon and a potent inducer of carcinogenesis. Many studies have reported that the carcinogenic effects of BaP might be due to its intermediate metabolites and to reactive oxygen species (ROS) that cause oxidative damage to the cells. However, the mechanisms of BaP-induced oxidative damage in cervical tissue are still not clear. We studied these mechanisms in female ICR mice treated with BaP either orally or intraperitoneally by measuring (1) several general biomarkers of oxidative stress in serum, (2) mitochondrial function in the cervix, and (3) the morphology of mitochondria in cervical tissue. BaP treatment (1) significantly lowered levels of vitamins A, C, and E and of glutathione; (2) reduced activities of superoxide dismutase, catalase, glutathione peroxidase, and glutathione S-transferases; and (3) significantly increased lipid peroxidation levels. In addition, significant increases in the levels of superoxide anion, hydrogen peroxide, and hydroxyl radical were observed. These results were confirmed by morphological changes in mitochondria and by decreases in membrane potential levels and in succinate dehydrogenase and malate dehydrogenase activities. The changes in these biomarkers and mitochondrial damage were BaP-dose-dependent and eventually induced both cell apoptosis and necrosis in cervical tissue. As mitochondria are the major sites of ROS generation, these findings show that mitochondrial decay greatly contributes to BaP-induced cervical damage.
Collapse
Affiliation(s)
- Meili Gao
- Institute of Cancer Research, Key Laboratory of Biomedical Information Engineering of the Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, China.
| | | | | | | | | | | | | |
Collapse
|
|
45
|
Nolan KA, Scott KA, Barnes J, Doncaster J, Whitehead RC, Stratford IJ. Pharmacological inhibitors of NAD(P)H quinone oxidoreductase, NQO1: structure/activity relationships and functional activity in tumour cells. Biochem Pharmacol 2010; 80:977-81. [PMID: 20599803 DOI: 10.1016/j.bcp.2010.06.024] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2010] [Revised: 06/11/2010] [Accepted: 06/14/2010] [Indexed: 12/22/2022]
Abstract
NAD(P)H quinone oxidoreductase (NQO1) has multiple functions in the cell including an ability to act as a detoxifying enzyme and as a protein chaperone. The latter property is particularly important in oncology as one of the client proteins of NQO1 is p53. The inhibitor, dicoumarol, is classically used to probe the biological properties of NQO1, but interpretation of enzyme function is compromised by the multiple "off-target" effects of this agent. Coumarin-based compounds that are more potent than dicoumarol as inhibitors of recombinant human NQO1 have been identified (Nolan et al., J Med Chem 2009;52:7142-56) The purpose of the work reported here is to demonstrate the functional activity of these agents for inhibiting NQO1 in cells. To do this, advantage was taken of the NQO1-mediated toxicity of the chemotherapeutic drug EO9 (Apaziquone). The toxicity of this drug is substantially reduced when the function of NQO1 is inhibited and many of the coumarin-based compounds are more efficient than dicoumarol for inhibiting EO9 toxicity. The ability to do this appears to be related to their capacity to inhibit NQO1 in cell free systems. In conclusion, agents have been identified that may be more pharmacologically useful than dicoumarol for probing the function of NQO1 in cells and tissues.
Collapse
Affiliation(s)
- Karen Ann Nolan
- School of Pharmacy and Pharmaceutical Sciences, University of Manchester and Manchester Cancer Research, Manchester, Oxford Road, Manchester, M13 9PT, UK
| | | | | | | | | | | |
Collapse
|
|
46
|
Abstract
There is ample evidence that shows an inverse relationship between consumption of fruit/vegetable-rich diets and the risk of cancer at various anatomical sites. In this review, we will assess and summarize recent advances on cancer prevention by resveratrol, a natural stilbenoid present in red grapes, peanuts, some common drinks, and dietary supplements. We will focus on data published within the past few years on in vivo model tumor animal studies that reinforce the chemopreventive efficacy of resveratrol against a multitude of cancers, as well as on its sensitization/enhancing activities against tumor cells when used in combination with established chemotherapeutic and pharmaceutical agents. In addition, we will review examples resveratrol-target proteins, denoted RTPs, including the 24-kDa cytosolic protein quinone reductase 2 (NQO2) discovered in our laboratory that may confer resveratrol responsiveness to cancer cells. We will discuss the possible role of NQO2 in mediating cancer prevention by resveratrol. Our analysis of published data strengthen support that resveratrol displays novel roles in various cellular processes, and help to establish an expanded molecular framework for cancer prevention by resveratrol in vivo.
Collapse
Affiliation(s)
| | - Joseph M. Wu
- Address for correspondence: Joseph M. Wu, Ph. D., Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA. Tel.: 914-594-4891; Fax: 914-594-4058;
| |
Collapse
|
|
47
|
Dinkova-Kostova AT, Talalay P. NAD(P)H:quinone acceptor oxidoreductase 1 (NQO1), a multifunctional antioxidant enzyme and exceptionally versatile cytoprotector. Arch Biochem Biophys 2010; 501:116-23. [PMID: 20361926 PMCID: PMC2930038 DOI: 10.1016/j.abb.2010.03.019] [Citation(s) in RCA: 553] [Impact Index Per Article: 36.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2010] [Revised: 03/17/2010] [Accepted: 03/25/2010] [Indexed: 12/30/2022]
Abstract
NAD(P)H:quinone acceptor oxidoreductase 1 (NQO1) is a widely-distributed FAD-dependent flavoprotein that promotes obligatory 2-electron reductions of quinones, quinoneimines, nitroaromatics, and azo dyes, at rates that are comparable with NADH or NADPH. These reductions depress quinone levels and thereby minimize opportunities for generation of reactive oxygen intermediates by redox cycling, and for depletion of intracellular thiol pools. NQO1 is a highly-inducible enzyme that is regulated by the Keap1/Nrf2/ARE pathway. Evidence for the importance of the antioxidant functions of NQO1 in combating oxidative stress is provided by demonstrations that induction of NQO1 levels or their depletion (knockout, or knockdown) are associated with decreased and increased susceptibilities to oxidative stress, respectively. Furthermore, benzene genotoxicity is markedly enhanced when NQO1 activity is compromised. Not surprisingly, human polymorphisms that suppress NQO1 activities are associated with increased predisposition to disease. Recent studies have uncovered protective roles for NQO1 that apparently are unrelated to its enzymatic activities. NQO1 binds to and thereby stabilizes the important tumor suppressor p53 against proteasomal degradation. Indeed, NQO1 appears to regulate the degradative fate of other proteins. These findings suggest that NQO1 may exercise a selective "gatekeeping" role in regulating the proteasomal degradation of specific proteins, thereby broadening the cytoprotective role of NQO1 far beyond its highly effective antioxidant functions.
Collapse
Affiliation(s)
- Albena T. Dinkova-Kostova
- Biomedical Research Institute, University of Dundee, Dundee, Scotland, UK
- Lewis B. and Dorothy Cullman Chemoprotection Center and Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Paul Talalay
- Lewis B. and Dorothy Cullman Chemoprotection Center and Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| |
Collapse
|
|
48
|
Evidence on the association between NQO1 Pro187Ser polymorphism and breast cancer risk in the current studies: a meta-analysis. Breast Cancer Res Treat 2010; 125:467-72. [PMID: 20526805 DOI: 10.1007/s10549-010-0966-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2010] [Accepted: 05/21/2010] [Indexed: 10/19/2022]
Abstract
Several molecular epidemiological studies were conducted in recent years to evaluate the association between NQO1 Pro187Ser polymorphism and breast cancer risk in diverse populations. However, the results remain conflicting rather than conclusive. This meta-analysis on 3177 cases with breast cancer and 4038 controls from seven published case-control studies showed that the 187Ser allele was not associated with a significantly increased risk of breast cancer (Ser versus Pro: P = 0.33, OR = 1.08, 95% CI = 0.92-1.28; Ser/Ser versus Pro/Pro: P = 0.58, OR = 1.16, 95% CI = 0.68-2.00; Ser/Ser versus Pro/Ser + Pro/Pro: P = 0.62, OR = 1.14, 95% CI = 0.68-1.90; Ser/Ser + Pro/Ser versus Pro/Pro: P = 0.30, OR = 1.07, 95% CI = 0.94-1.22). In the stratified analysis by ethnicity, we found that the Pro187Ser polymorphism was associated with increased breast cancer risk in Caucasians in the additive genetic model and dominant genetic model (P = 0.03, OR = 1.13, 95% CI = 1.01-1.26; P = 0.03, OR = 1.15, 95% CI = 1.01-1.30, respectively), whereas no significant in Asians (P = 0.44, OR = 0.94, 95% CI = 0.80-1.10) and postmenopausal women (P = 0.99, OR = 1.00, 95% CI = 0.84-1.19). The results suggest that NQO1 Pro187Ser polymorphism may contribute to breast cancer development in Caucasians.
Collapse
|
|
49
|
Kundu JK, Surh YJ. Nrf2-Keap1 signaling as a potential target for chemoprevention of inflammation-associated carcinogenesis. Pharm Res 2010; 27:999-1013. [PMID: 20354764 DOI: 10.1007/s11095-010-0096-8] [Citation(s) in RCA: 129] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2009] [Accepted: 02/15/2010] [Indexed: 12/12/2022]
Abstract
Persistent inflammatory tissue damage is causally associated with each stage of carcinogenesis. Inflammation-induced generation of reactive oxygen species, reactive nitrogen species, and other reactive species not only cause DNA damage and subsequently mutations, but also stimulate proliferation of initiated cells and even metastasis and angiogenesis. Induction of cellular cytoprotective enzymes (e.g., heme oxygenase-1, NAD(P)H:quinone oxidoreductase, superoxide dismutase, glutathione-S-transferase, etc.) has been shown to mitigate aforementioned events implicated in inflammation-induced carcinogenesis. A unique feature of genes encoding these cytoprotective enzymes is the presence of a cis-acting element, known as antioxidant response element (ARE) or electrophile response element (EpRE), in their promoter region. A stress-responsive transcription factor, nuclear factor erythroid-2-related factor-2 (Nrf2), initially recognized as a key transcriptional regulator of various cytoprotective enzymes, is known to play a pivotal role in cellular defense against inflammatory injuries. Activation of Nrf2 involves its release from the cytosolic repressor Kelch-like ECH-associated protein-1 (Keap1) and subsequent stabilization and nuclear localization for ARE/EpRE binding. Genetic or pharmacologic inactivation of Nrf2 has been shown to abolish cytoprotective capability and to aggravate experimentally induced inflammatory injuries. Thus, Nrf2-mediated cytoprotective gene induction is an effective strategy for the chemoprevention of inflammation-associated carcinogenesis.
Collapse
Affiliation(s)
- Joydeb Kumar Kundu
- College of Pharmacy, Seoul National University, 599 Kwanak-ro, Kwanak-ku, Seoul 151-742, South Korea
| | | |
Collapse
|
|
50
|
Shen J, Barrios RJ, Jaiswal AK. Inactivation of the quinone oxidoreductases NQO1 and NQO2 strongly elevates the incidence and multiplicity of chemically induced skin tumors. Cancer Res 2010; 70:1006-14. [PMID: 20103645 DOI: 10.1158/0008-5472.can-09-2938] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
The cytosolic quinone oxidoreductases NQO1 and NQO2 protect cells against oxidative stress by detoxifying quinones and preventing redox cycling. In this study, we used double knockout (DKO) mice deficient for NQO1 and NQO2 to investigate the role of these antioxidative enzymes in a two-stage model of inflammatory skin carcinogenesis. In this model, tumors are caused by exposure to topical carcinogen dimethylbenz(a)anthracene or benzo(a)pyrene (BP) followed by twice weekly application of proinflammatory phorbol 12-myristate 13-acetate. On this classic chemical carcinogenesis protocol, DKO mice showed a significantly higher skin tumor frequency and multiplicity compared with control wild-type or single knockout mice. Analysis of skin from wild-type and DKO mice exposed to BP for 6, 12, or 24 hours revealed a relative delay in the activation of p53, p63, p19ARF, and apoptosis in DKO mice, consistent with a negative modifier role for NQO1/NQO2 in carcinogenesis. Our findings offer genetic evidence of the significance of quinone oxidoreductases NQO1 and NQO2 in limiting chemical skin carcinogenesis.
Collapse
Affiliation(s)
- Jun Shen
- Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA
| | | | | |
Collapse
|