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1.
Nat Commun ; 11(1): 5436, 2020 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-33116123

RESUMO

Harmful effects of high fructose intake on health have been widely reported. Although fructose is known to promote cancer, little is known about the underlying mechanisms. Here, we found that fructose triggers breast cancer metastasis through the ketohexokinase-A signaling pathway. Molecular experiments showed that ketohexokinase-A, rather than ketohexokinase-C, is necessary and sufficient for fructose-induced cell invasion. Ketohexokinase-A-overexpressing breast cancer was found to be highly metastatic in fructose-fed mice. Mechanistically, cytoplasmic ketohexokinase-A enters into the nucleus during fructose stimulation, which is mediated by LRRC59 and KPNB1. In the nucleus, ketohexokinase-A phosphorylates YWHAH at Ser25 and the YWHAH recruits SLUG to the CDH1 promoter, which triggers cell migration. This study provides the effect of nutrition on breast cancer metastasis. High intake of fructose should be restricted in cancer patients to reduce the risk of metastasis. From a therapeutic perspective, the ketohexokinase-A signaling pathway could be a potential target to prevent cancer metastasis.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Frutoquinases/metabolismo , Frutose/administração & dosagem , Frutose/metabolismo , Proteínas 14-3-3/antagonistas & inibidores , Proteínas 14-3-3/genética , Proteínas 14-3-3/metabolismo , Animais , Carcinógenos/administração & dosagem , Carcinógenos/metabolismo , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Feminino , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Invasividade Neoplásica/patologia , Metástase Neoplásica/patologia , Fosforilação , Transdução de Sinais , beta Carioferinas/metabolismo
2.
Sheng Wu Gong Cheng Xue Bao ; 36(8): 1640-1649, 2020 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-32924362

RESUMO

Ethyl carbamate (EC) is a carcinogen detected in fermented foods and alcohol beverages. Excessive intake of EC is possibly harmful to health. Enzymatic degradation is one of the most effective approaches for reducing EC in fermented foods. Urease catalyzes the hydrolysis of both EC and urea. This confers urease a good application prospect in reducing EC and its precursor urea in fermented foods. Currently, degradation of EC in alcohol beverages by urease is inefficient due to its low urethanase activity and poor affinity to EC. Urease from Bacillus amyloliquefaciens JP-21 was successfully expressed in Escherichia coli at the level of 3 292 U/L urease and 227.3 U/L urethanase. Two key residues M326 and M374 were characterized that might block the binding of enzyme to EC, through simulating docking the structure of catalytic subunit UreC of urease with EC. Three mutants (M374A, M374T and M326V) of urease with improved urethanase activity were obtained by performing point saturated mutagenesis approach. Using EC as the substrate, Km values of M374A, M374T and M326V were detected to be 101.8 mmol/L, 129.5 mmol/L and 121.7 mmol/L, respectively, which were decreased by 37.47%-50.82% compared with that of the wild type urease. These mutants can degrade more than 97% of urea in rice wine and mutant M374T shows the highest degradation of EC in rice wine. EC content in rice wine was reduced from 525 µg/L to 393 µg/L by using M374T, and the EC degradation rate of it is 0.97 folds higher than that of the wild type urease. The results are of great significance for engineering the catalytic properties of urease and improving its industrial properties, and lays a good foundation for developing strategies to reducing microbial metabolic ammonia (amine) hazards in fermented foods.


Assuntos
Bacillus amyloliquefaciens , Microbiologia de Alimentos , Oryza , Urease , Uretana , Bacillus amyloliquefaciens/enzimologia , Bacillus amyloliquefaciens/genética , Carcinógenos/metabolismo , Mutagênese Sítio-Dirigida , Urease/genética , Urease/metabolismo , Uretana/metabolismo , Vinho/microbiologia
3.
Proc Natl Acad Sci U S A ; 117(35): 21576-21587, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32801214

RESUMO

Toxic environmental carcinogens promote cancer via genotoxic and nongenotoxic pathways, but nongenetic mechanisms remain poorly characterized. Carcinogen-induced apoptosis may trigger escape from dormancy of microtumors by interfering with inflammation resolution and triggering an endoplasmic reticulum (ER) stress response. While eicosanoid and cytokine storms are well-characterized in infection and inflammation, they are poorly characterized in cancer. Here, we demonstrate that carcinogens, such as aflatoxin B1 (AFB1), induce apoptotic cell death and the resulting cell debris stimulates hepatocellular carcinoma (HCC) tumor growth via an "eicosanoid and cytokine storm." AFB1-generated debris up-regulates cyclooxygenase-2 (COX-2), soluble epoxide hydrolase (sEH), ER stress-response genes including BiP, CHOP, and PDI in macrophages. Thus, selective cytokine or eicosanoid blockade is unlikely to prevent carcinogen-induced cancer progression. Pharmacological abrogation of both the COX-2 and sEH pathways by PTUPB prevented the debris-stimulated eicosanoid and cytokine storm, down-regulated ER stress genes, and promoted macrophage phagocytosis of debris, resulting in suppression of HCC tumor growth. Thus, inflammation resolution via dual COX-2/sEH inhibition is an approach to prevent carcinogen-induced cancer.


Assuntos
Citocinas/metabolismo , Eicosanoides/metabolismo , Neoplasias Hepáticas/metabolismo , Aflatoxina B1/efeitos adversos , Animais , Apoptose , Carcinogênese/metabolismo , Carcinógenos/metabolismo , Carcinoma Hepatocelular/metabolismo , Linhagem Celular , Ciclo-Oxigenase 2/metabolismo , Citocinas/imunologia , Progressão da Doença , Eicosanoides/imunologia , Epóxido Hidrolases/metabolismo , Células Hep G2 , Humanos , Inflamação/metabolismo , Neoplasias Hepáticas/fisiopatologia , Macrófagos/metabolismo , Camundongos , Processos Neoplásicos
4.
Chemosphere ; 252: 126644, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32443284

RESUMO

Pendimethalin, one of the dinitroaniline group herbicides, is applied for controlling weeds in cereals, legumes and vegetable crops, and has been classified as possible human carcinogen. It is indicated that pendimethalin should arise risks of developing some cancer types; however, there is no data on the effects of pendimethalin on pancreatic cancer-induced inflammation. Injuries resulting from by acute pancreatitis attacks and inflammation are significant factors in the development of pancreatic cancer. Therefore, we investigated whether pendimethalin triggers inflammation as a mechanism of pancreatic cancer development. Parameters related to pancreatic activation, oxidative stress, and inflammation were measured in the human pancreatic (PANC-1) cell line. In the range of 0-100 µM, the levels of chymotrypsin decreased. It should be indicated that the reason for the decrease in chymotrypsin may be the high rates of cell death (20%) observed in the high concentration levels. We observed that pendimethalin significantly induced oxidative damage, while levels of interleukin-6 (IL-6) and interleukin-8 (IL-8) did not change. The obtained results may draw attention to the usage and possible toxic effect of pendimethalin due to oxidative damage induction; however, detailed inflammation mechanisms and other cancer pathways should be investigated.


Assuntos
Compostos de Anilina/toxicidade , Carcinógenos/toxicidade , Herbicidas/toxicidade , Neoplasias Pancreáticas/induzido quimicamente , Doença Aguda , Carcinógenos/metabolismo , Herbicidas/metabolismo , Humanos , Inflamação/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Pâncreas/metabolismo
5.
Mol Cell Biochem ; 468(1-2): 185-193, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32200471

RESUMO

MYB Proto-Oncogene Like 2 (MYBL2) is a highly conserved member of the Myb family of transcription factors and plays a critical role in regulating cell proliferation and survival. Here we show that overexpression of MYBL2 is frequently observed in lung adenocarcinoma (LUAD) and significantly correlates with advanced stage and poor patient survival. Knockdown of MYBL2 induced apoptosis in lung cancer cells and resulted in significant inhibition of cell proliferation, migration, and invasion. Notably, we identified Non-SMC Condensin I Complex Subunit H (NCAPH) gene as a direct target of MYBL2. NCAPH expression is highly correlated with that of MYBL2 in LUAD cases and is tightly affected by MYBL2 knockdown or overexpression in vitro. Chromatin immunoprecipitation (ChIP) assays also showed that MYBL2 directly binds to the transcription start site (TSS) of NCAPH. Moreover, we provided evidence that NCAPH functions as an oncogene in lung cancer and overexpression of NCAPH could partially rescue cell death and migration blockage induced by MYBL2 knockdown. Together, these results suggest that overexpression of MYBL2 promotes proliferation and migration of lung cancer cells via upregulating NCAPH, establishing their roles as novel prognostic biomarkers as well as potential therapeutic targets for the disease.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proteínas de Ciclo Celular/metabolismo , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias Pulmonares/metabolismo , Proteínas Nucleares/metabolismo , Transativadores/metabolismo , Células A549 , Apoptose/genética , Biomarcadores Tumorais/genética , Carcinógenos/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas de Ciclo Celular/genética , Imunoprecipitação da Cromatina , Regulação Neoplásica da Expressão Gênica/genética , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Proteínas Nucleares/genética , Ligação Proteica , Transativadores/genética , Ativação Transcricional/genética , Regulação para Cima
6.
Chemistry ; 26(43): 9459-9465, 2020 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-32167602

RESUMO

Protein folding quality control in cells requires the activity of a class of proteins known as molecular chaperones. Heat shock protein-90 (Hsp90), a multidomain ATP driven molecular machine, is a prime representative of this family of proteins. Interactions between Hsp90, its co-chaperones, and client proteins have been shown to be important in facilitating the correct folding and activation of clients. Hsp90 levels and functions are elevated in tumor cells. Here, we computationally predict the regions on the native structures of clients c-Abl, c-Src, Cdk4, B-Raf and Glucocorticoid Receptor, that have the highest probability of undergoing local unfolding, despite being ordered in their native structures. Such regions represent potential ideal interaction points with the Hsp90-system. We synthesize mimics spanning these regions and confirm their interaction with partners of the Hsp90 complex (Hsp90, Cdc37 and Aha1) by Nuclear Magnetic Resonance (NMR). Designed mimics selectively disrupt the association of their respective clients with the Hsp90 machinery, leaving unrelated clients unperturbed and causing apoptosis in cancer cells. Overall, selective targeting of Hsp90 protein-protein interactions is achieved without causing indiscriminate degradation of all clients, setting the stage for the development of therapeutics based on specific chaperone:client perturbation.


Assuntos
Carcinógenos/química , Proteínas de Ciclo Celular/química , Chaperoninas/química , Proteínas de Choque Térmico HSP90/química , Chaperonas Moleculares/química , Carcinógenos/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Dobramento de Proteína
7.
Chem Biol Interact ; 322: 109056, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32198084

RESUMO

Cytochrome P450 (P450) 2E1 is the major P450 enzyme involved in ethanol metabolism. That role is shared with two other enzymes that oxidize ethanol, alcohol dehydrogenase and catalase. P450 2E1 is also involved in the bioactivation of a number of low molecular weight cancer suspects, as validated in vivo in mouse models where cancers could be attenuated by deletion of Cyp2e1. P450 2E1 does not have a role in global production of reactive oxygen species but localized roles are possible, e.g. in mitochondria. The structures, conformations, and catalytic mechanisms of P450 2E1 have some unusual features among P450s. The concentration of hepatic P450 varies ≥10-fold among humans, possibly in part due to single nucleotide variants. The level of P450 2E1 may have relevance in the rates of oxidation of drugs, particularly acetaminophen and anesthetics.


Assuntos
Citocromo P-450 CYP2E1/metabolismo , Neoplasias/patologia , Acetaminofen/química , Acetaminofen/metabolismo , Animais , Carcinógenos/química , Carcinógenos/metabolismo , Citocromo P-450 CYP2E1/deficiência , Citocromo P-450 CYP2E1/genética , Etanol/química , Etanol/metabolismo , Humanos , Cinética , Mitocôndrias/metabolismo , Neoplasias/metabolismo , Espécies Reativas de Oxigênio/metabolismo
8.
Chemosphere ; 252: 126484, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32199166

RESUMO

An increased risk of developing colorectal cancer has been associated with exposure to persistent organic pollutants (POPs) and alteration in the gut bacterial community. However, there is limited understanding about the impact of maternal exposure to POPs on colorectal cancer and gut microbiota. This study characterized the influence of exposure to a human relevant mixture of POPs during gestation and lactation on colorectal cancer, intestinal metabolite composition and microbiota in the A/J Min/+ mouse model. Surprisingly, the maternal POP exposure decreased colonic tumor burden, as shown by light microscopy and histopathological evaluation, indicating a restriction of colorectal carcinogenesis. 1H nuclear magnetic resonance spectroscopy-based metabolomic analysis identified alterations in the metabolism of amino acids, lipids, glycerophospholipids and energy in intestinal tissue. In addition, 16S rRNA sequencing of gut microbiota indicated that maternal exposure modified fecal bacterial composition. In conclusion, the results showed that early-life exposure to a mixture of POPs reduced colorectal cancer initiation and promotion, possibly through modulation of the microbial and biochemical environment. Further studies should focus on the development of colorectal cancer after combined maternal and dietary exposures to environmentally relevant low-dose POP mixtures.


Assuntos
Carcinógenos/metabolismo , Poluentes Ambientais/metabolismo , Animais , Carcinogênese , Carcinógenos/toxicidade , Neoplasias do Colo , Neoplasias Colorretais/induzido quimicamente , Poluentes Ambientais/toxicidade , Feminino , Microbioma Gastrointestinal/genética , Humanos , Lactação , Exposição Materna/estatística & dados numéricos , Metabolômica , Camundongos , Camundongos Endogâmicos , Microbiota , RNA Ribossômico 16S
9.
Life Sci ; 253: 117584, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32220623

RESUMO

Accumulating recent studies have demonstrated the preventive and therapeutic effects of polyphonic compounds such as quercetin in colorectal cancer. Therefore, we aimed to evaluate the underlying mechanisms for positive effects of quercetin in rats with 1,2-dimethylhydrazine (DMH)- induced colorectal cancer. For this purpose, male Wistar rats were classified as 6 groups, including group 1 without any intervention, group 2 as quercetin received rats (50 mg/kg), groups 3 as DMH received rats (20 mg/kg) group 4-6 DMH and quercetin received rats. DNA damage, DNA repair, the expression levels and activities of enzymic antioxidants, non-enzymic antioxidants, and NRF2/Keap1 signaling were evaluated in colon tissues of all groups. Our results showed significant suppression of DNA damage and induction of DNA repair in DMH + Quercetin groups, particularly in entire-period in comparison to other groups (p < .05). The expression levels and activities of enzymic and non-enzymic antioxidants were increased in DMH + Quercetin groups (p < .05). Lipid and protein peroxidation were significantly suppressed in DMH + Quercetin groups (p < .05). In addition, quercetin also modulated NRF2/Keap1 signaling and its targets, detoxifying enzymes in DMH + Quercetin groups. Our finding demonstrated that quercetin supplementation effectively reversed DMH-mediated oxidative stress and DNA damage through targeting NRF2/Keap1 signaling pathway.


Assuntos
1,2-Dimetilidrazina/metabolismo , Carcinógenos/metabolismo , Neoplasias do Colo/tratamento farmacológico , Fator 2 Relacionado a NF-E2/metabolismo , Quercetina/química , 1,2-Dimetilidrazina/toxicidade , Animais , Antioxidantes/química , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Carcinógenos/química , Carcinógenos/toxicidade , Catalase/metabolismo , Dano ao DNA/efeitos dos fármacos , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Lipídeos/química , Masculino , Neoplasias Experimentais , Estresse Oxidativo/efeitos dos fármacos , Quercetina/metabolismo , Quercetina/farmacologia , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio , Transdução de Sinais
10.
Chemosphere ; 249: 126097, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32078851

RESUMO

Benz(a)anthracene (BaA) is a polycyclic aromatic hydrocarbons (PAHs), that belongs to a group of carcinogenic and mutagenic persistent organic pollutants found in a variety of ecological habitats. In this study, the efficient biodegradation of BaA by a green alga Chlamydomonas reinhardtii (C. reinhardtii) CC-503 was investigated. The results showed that the growth of C. reinhardtii was hardly affected with an initial concentration of 10 mg/L, but was inhibited significantly under higher concentrations of BaA (>30 mg/L) (p < 0.05). We demonstrated that the relatively high concentration of 10 mg/L BaA was degraded completely in 11 days, which indicated that C. reinhardtii had an efficient degradation system. During the degradation, the intermediate metabolites were determined to be isomeric phenanthrene or anthracene, 2,6-diisopropylnaphthalene, 1,3-diisopropylnaphthalene, 1,7-diisopropylnaphthalene, and cyclohexanol. The enzymes involved in the degradation included the homogentisate 1,2-dioxygenase (HGD), the carboxymethylenebutenolidase, the ribulose 1,5-bisphosphate carboxylase/oxygenase (Rubisco) and the ubiquinol oxidase. The respective genes encoding these proteins were significantly up-regulated ranging from 3.17 fold to 13.03 fold and the activity of enzymes, such as HGD and Rubisco, was significantly induced up to 4.53 and 1.46 fold (p < 0.05), during the BaA metabolism. This efficient degradation ability suggests that the green alga C. reinhardtii CC-503 may be a sustainable candidate for PAHs remediation.


Assuntos
Antracenos/metabolismo , Biodegradação Ambiental , Chlamydomonas reinhardtii/metabolismo , Poluentes Ambientais/metabolismo , Benzo(a)Antracenos/metabolismo , Carcinógenos/metabolismo , Dioxigenases/metabolismo , Fenantrenos , Hidrocarbonetos Policíclicos Aromáticos/metabolismo
11.
Cancer Immunol Immunother ; 69(4): 549-558, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31970439

RESUMO

In oropharyngeal squamous cell carcinoma (OPSCC), the relationships between immune responses, carcinogens, and prognoses are not clarified yet. Here, we retrospectively reviewed the pathology samples of 46 OPSCC patients, and used p16 to determine their human papillomavirus (HPV) status. The Cancer Genome Atlas (TCGA) database was also analyzed for further comparison. The immunofluorescence staining of proinflammatory cytokines showed that high interferon gamma (IFNγ; T helper 1; Th1), low interleukin 4 (IL4; T helper 2; Th2), low thymic stromal lymphopoietin (TSLP; Th2), and low transforming growth factor beta (TGFß; T regulatory; Treg) expressions were good prognostic factors for OPSCC. p16-positive OPSCC showed higher Th1, lower Th2/Treg proinflammatory cytokine expressions, and a better prognosis than p16-negative OPSCC. In smokers alone, although p16-positive OPSCC smokers showed weaker Th2/Treg predominant cytokine expressions than p16-negative OPSCC smokers, the prognoses of both groups were equally poor. As for p16-positive OPSCC patients alone, p16-positive nonsmokers showed a significantly better prognosis than p16-positive smokers, but the immune responses of both groups were all weakly Th2/Treg predominant. Overall, higher Th1 and lower Th2/Treg proinflammatory cytokine expressions are associated with a better prognosis for OPSCC. HPV may be related to increased Th1, decreased Th2/Treg responses, and a good prognosis, while smoking may be related to increased Th2/Treg, decreased Th1 responses, and a poor prognosis in OPSCC. The impact of smoking on immune deviation may be weaker than that of HPV, but the impact of smoking on prognosis may be stronger than that of HPV in OPSCC.


Assuntos
Carcinógenos/metabolismo , Carcinoma de Células Escamosas/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Citocinas/metabolismo , Neoplasias Orofaríngeas/metabolismo , Infecções por Papillomavirus/metabolismo , Adulto , Idoso , Carcinoma de Células Escamosas/complicações , Feminino , Papillomavirus Humano 16/fisiologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neoplasias Orofaríngeas/complicações , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/virologia , Estudos Retrospectivos , Fumar
12.
Ecotoxicol Environ Saf ; 191: 110157, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31954218

RESUMO

Urban parks and schools sever as the mainly activity areas for children, but risk assessment posed by heavy metals (HMs) from soil and dust in these area has rarely been investigated. In this study, six urban parks and seven schools in Jiaozuo, China, were taken as research objects to understand the contamination level and bioaccessibility of HMs from soil and dust in urban parks and schools. The results indicated that Zn, Cu, Pb, Cd, As, Ni and Co from soil and dust were above the background values, especially Zn and Cd in dust, and As and Cd in soil. Serious Cd pollution was discovered, and respective Cd concentrations in soil and dust were 17.83 and 7.52 times the background value. Additionally, the average concentration and bioaccessibility of Zn, Mn, Pb, Cd, Cr, Ni and Co in dust were both higher than in soil. High concentration and high bioaccessibility of HMs in dust suggested that HMs contamination were serious and universal in Jiaozuo. The concentrations of most HMs were higher in the gastric phase, except for Cu and Cd which remained higher in the intestinal phase. Both in the gastric phase and intestinal phase, Mn, As and Cd in soil and dust both have high bioaccessibility which all exceed 10%. The carcinogenic and non-carcinogenic risks base on the total HMs for children (soil: 7.93, 1.96E-05; dust: 6.44, 3.58E-05) were greater than those for adults (soil: 6.35E-01, 1.32E-05; dust: 5.06E-01, 2.42E-05), and urban parks and schools posed high potential risk for children. Therefore, assessment the risk posed by HMs contamination of soil and dust in urban parks and schools is vital and urgent for children.


Assuntos
Poeira/análise , Exposição Ambiental/análise , Metais Pesados/análise , Poluentes do Solo/análise , Adulto , Disponibilidade Biológica , Carcinógenos/análise , Carcinógenos/metabolismo , Criança , China , Exposição Ambiental/efeitos adversos , Humanos , Metais Pesados/metabolismo , Parques Recreativos , Medição de Risco , Instituições Acadêmicas , Poluentes do Solo/metabolismo
13.
Mol Cells ; 43(2): 176-181, 2020 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-31991537

RESUMO

The RUNX transcription factors serve as master regulators of development and are frequently dysregulated in human cancers. Among the three family members, RUNX3 is the least studied, and has long been considered to be a tumor-suppressor gene in human cancers. This idea is mainly based on the observation that RUNX3 is inactivated by genetic/epigenetic alterations or protein mislocalization during the initiation of tumorigenesis. Recently, this paradigm has been challenged, as several lines of evidence have shown that RUNX3 is upregulated over the course of tumor development. Resolving this paradox and understanding how a single gene can exhibit both oncogenic and tumor-suppressive properties is essential for successful drug targeting of RUNX. We propose a simple explanation for the duality of RUNX3: p53 status. In this model, p53 deficiency causes RUNX3 to become an oncogene, resulting in aberrant upregulation of MYC.


Assuntos
Carcinógenos/metabolismo , Subunidade alfa 3 de Fator de Ligação ao Core/genética , Fatores de Transcrição/metabolismo , Proteína Supressora de Tumor p53/deficiência , Humanos
14.
Pharmacogenet Genomics ; 30(3): 61-65, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31895247

RESUMO

Arylamine N-acetyltransferases are xenobiotic-metabolizing enzymes responsible for detoxification of many drugs and carcinogens. Two N-acetyltransferase proteins (NAT1 and NAT2) are expressed in humans and they both N-acetylate aromatic amine carcinogens such as 4-aminobiphenyl. Arylamines such as 4-aminobiphenyl represent a large class of chemical carcinogens. Exposure to 4-aminobiphenyl occurs in the chemical, dye and rubber industries as well as in hair dyes, paints, and cigarette smoke. NAT2 is subject to a genetic polymorphism resulting in rapid, intermediate and slow acetylator phenotypes. We investigated the role of the NAT2 genetic polymorphisms on the N-acetylation of 4-aminobiphenyl in cryopreserved human hepatocytes in which NAT2 genotype and deduced phenotype were determined. Differences in sulfamethazine (selectively N-acetylated via NAT2) and 4-aminobiphenyl (N-acetylated by both NAT1 and NAT2) N-acetylation rates among rapid, intermediate, and slow NAT2 acetylator genotypes were tested for significance by one-way analysis of variance. In vitro 4-aminobiphenyl N-acetyltransferase activities differed significantly between rapid, intermediate and slow acetylators at 10 µM (P = 0.0102) or 100 µM (P = 0.0028). N-acetylation of 4-aminobiphenyl in situ also differed significantly between human hepatocytes from rapid, intermediate, and slow acetylators at 10 µM (P = 0.0015) and 100 µM (P = 0.0216). A gene dose-response relationship was exhibited as intermediate acetylators catalyzed 4-aminobiphenyl N-acetylation both in vitro and in situ at rates arithmetically between rapid and slow acetylators. In conclusion, N-acetylation of 4-aminobiphenyl is NAT2 genotype-dependent in human hepatocytes. These results suggest refinement of the exposure limit and safety for arylamine carcinogens according to NAT2 genotype.


Assuntos
Compostos de Aminobifenil/metabolismo , Arilamina N-Acetiltransferase/genética , Arilamina N-Acetiltransferase/metabolismo , Hepatócitos/enzimologia , Acetilação , Carcinógenos/metabolismo , Criopreservação , Estudos de Associação Genética , Genótipo , Hepatócitos/metabolismo , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , Fenótipo , Polimorfismo Genético , Sulfametazina/metabolismo
15.
Environ Mol Mutagen ; 61(1): 94-113, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31709603

RESUMO

We recently published a next generation framework for assessing the risk of genomic damage via exposure to chemical substances. The framework entails a systematic approach with the aim to quantify risk levels for substances that induce genomic damage contributing to human adverse health outcomes. Here, we evaluated the utility of the framework for assessing the risk for industrial chemicals, using the case of benzene. Benzene is a well-studied substance that is generally considered a genotoxic carcinogen and is known to cause leukemia. The case study limits its focus on occupational and general population health as it relates to benzene exposure. Using the framework as guidance, available data on benzene considered relevant for assessment of genetic damage were collected. Based on these data, we were able to conduct quantitative analyses for relevant data sets to estimate acceptable exposure levels and to characterize the risk of genetic damage. Key observations include the need for robust exposure assessments, the importance of information on toxicokinetic properties, and the benefits of cheminformatics. The framework points to the need for further improvement on understanding of the mechanism(s) of action involved, which would also provide support for the use of targeted tests rather than a prescribed set of assays. Overall, this case study demonstrates the utility of the next generation framework to quantitatively model human risk on the basis of genetic damage, thereby enabling a new, innovative risk assessment concept. Environ. Mol. Mutagen. 61:94-113, 2020. © 2019 The Authors. Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society.


Assuntos
Benzeno/toxicidade , Carcinógenos/toxicidade , Mutagênese/efeitos dos fármacos , Mutagênicos/toxicidade , Animais , Benzeno/metabolismo , Carcinógenos/metabolismo , Dano ao DNA/efeitos dos fármacos , Exposição Ambiental/efeitos adversos , Humanos , Leucemia/induzido quimicamente , Leucemia/genética , Testes de Mutagenicidade/métodos , Mutagênicos/metabolismo , Exposição Ocupacional/efeitos adversos , Medição de Risco/métodos
16.
Environ Mol Mutagen ; 61(2): 235-245, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31490564

RESUMO

Carcinogenic aromatic amines such as 4-aminobiphenyl (ABP) and 2-aminofluorene (AF) require metabolic activation to form electrophilic intermediates that mutate DNA leading to carcinogenesis. Bioactivation of these carcinogens includes N-hydroxylation catalyzed by CYP1A2 followed by O-acetylation catalyzed by arylamine N-acetyltransferase 2 (NAT2). To better understand the role of NAT2 genetic polymorphism in ABP- and AF-induced mutagenesis and DNA damage, nucleotide excision repair-deficient (UV5) Chinese hamster ovary (CHO) cells were stably transfected with human CYP1A2 and either NAT2*4 (rapid acetylator) or NAT2*5B (slow acetylator) alleles. ABP and AF both caused significantly (P < 0.001) greater mutagenesis measured at the hypoxanthine phosphoribosyl transferase (hprt) locus in the UV5/CYP1A2/NAT2*4 acetylator cell line compared to the UV5, UV5/CYP1A2, and UV5/CYP1A2/NAT2*5B cell lines. ABP- and AF-induced hprt mutant cDNAs were sequenced and over 80% of the single-base substitutions were at G:C base pairs. DNA damage also was quantified by γH2AX in-cell western assays and by identification and quantification of the two predominant DNA adducts, N-(deoxyguanosin-8-yl)-4-aminobiphenyl (dG-C8-ABP) and N-(deoxyguanosin-8-yl)-2-aminofluorene (dG-C8-AF) by liquid chromatography-mass spectrometry. DNA damage and adduct levels were dose-dependent, correlated highly with levels of hprt mutants, and were significantly (P < 0.0001) greater in the UV5/CYP1A2/NAT2*4 rapid acetylator cell line following treatment with ABP or AF as compared to all other cell lines. Our findings provide further clarity on the importance of O-acetylation in CHO mutagenesis assays for aromatic amines. They provide evidence that NAT2 genetic polymorphism modifies aromatic amine-induced DNA damage and mutagenesis that should be considered in human risk assessments following aromatic amine exposures. Environ. Mol. Mutagen. 61:235-245, 2020. © 2019 Wiley Periodicals, Inc.


Assuntos
Compostos de Aminobifenil/metabolismo , Arilamina N-Acetiltransferase/genética , Carcinógenos/metabolismo , Fluorenos/metabolismo , Polimorfismo Genético , Acetilação , Compostos de Aminobifenil/toxicidade , Animais , Arilamina N-Acetiltransferase/metabolismo , Células CHO , Carcinógenos/toxicidade , Cricetinae , Cricetulus , Dano ao DNA/efeitos dos fármacos , Fluorenos/toxicidade , Humanos , Mutagênese/efeitos dos fármacos , Testes de Mutagenicidade
17.
Food Chem ; 302: 125339, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31419771

RESUMO

Intake of red and processed meat has been suspected to increase colorectal cancer risk potentially via endogenous formation of carcinogenic N-nitroso compounds or increased lipid and protein oxidation. Here we investigated the effect of inulin fortification of a pork sausage on these parameters. For four weeks, healthy Sprague-Dawley rats (n = 30) were fed one of three diets: inulin-fortified pork sausage, control pork sausage or a standard chow diet. Fecal content of apparent total N-nitroso compounds (ATNC), nitrosothiols and nitrosyl iron compounds (FeNO) were analyzed in addition to liver metabolism and oxidation products formed in liver, plasma and diets. Intriguingly, inulin fortification reduced fecal ATNC (p = 0.03) and FeNO (p = 0.04) concentrations. The study revealed that inulin fortification of processed meat could be a strategy to reduce nitroso compounds formed endogenously after consumption.


Assuntos
Alimentos Fortificados , Inulina/farmacologia , Produtos da Carne , Compostos Nitrosos/metabolismo , Ração Animal , Animais , Carcinógenos/análise , Carcinógenos/metabolismo , Fezes/química , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Espectroscopia de Ressonância Magnética , Compostos Nitrosos/análise , Ratos Sprague-Dawley , Carne Vermelha , Suínos
18.
Artigo em Inglês | MEDLINE | ID: mdl-31709196

RESUMO

Objective: The human intestinal microbiome plays an important role in inflammatory bowel disease (IBD) and colorectal cancer (CRC) development. One of the first discovered bacterial mediators involves Bacteroides fragilis toxin (BFT, also named as fragilysin), a metalloprotease encoded by enterotoxigenic Bacteroides fragilis (ETBF) that causes barrier disruption and inflammation of the colon, leads to tumorigenesis in susceptible mice, and is enriched in the mucosa of IBD and CRC patients. Thus, targeted inhibition of BFT may benefit ETBF carrying patients. Design: By applying two complementary in silico drug design techniques, drug repositioning and molecular docking, we predicted potential BFT inhibitory compounds. Top candidates were tested in vitro on the CRC epithelial cell line HT29/c1 for their potential to inhibit key aspects of BFT activity, being epithelial morphology changes, E-cadherin cleavage (a marker for barrier function) and increased IL-8 secretion. Results: The primary bile acid and existing drug chenodeoxycholic acid (CDCA), currently used for treating gallstones, cerebrotendinous xanthomatosis, and constipation, was found to significantly inhibit all evaluated cell responses to BFT exposure. The inhibition of BFT resulted from a direct interaction between CDCA and BFT, as confirmed by an increase in the melting temperature of the BFT protein in the presence of CDCA. Conclusion: Together, our results show the potential of in silico drug discovery to combat harmful human and microbiome-derived proteins and more specifically suggests a potential for retargeting CDCA to inhibit the pro-oncogenic toxin BFT.


Assuntos
Carcinógenos/metabolismo , Transformação Celular Neoplásica , Descoberta de Drogas , Reposicionamento de Medicamentos , Microbioma Gastrointestinal , Toxinas Biológicas , Transformação Celular Neoplásica/induzido quimicamente , Transformação Celular Neoplásica/efeitos dos fármacos , Endotoxinas/química , Endotoxinas/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Metaloendopeptidases/química , Metaloendopeptidases/farmacologia , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Relação Estrutura-Atividade , Toxinas Biológicas/efeitos adversos , Toxinas Biológicas/biossíntese
19.
Aging (Albany NY) ; 11(21): 9778-9793, 2019 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-31727867

RESUMO

Globally, epithelial ovarian cancer (EOC) is the most common gynecological malignancy with poor prognosis. The expression and oncogenic roles of ubiquitin specific peptidase 5 (USP5) have been reported in several cancers except EOC. In the current study, USP5 amplification was highly prevalent in patients with EOC and associated with higher mRNA expression of USP5. USP5 amplification and overexpression was positively correlated with poor prognosis of patients of ovarian serous carcinomas. Disruption of USP5 profoundly repressed cell proliferation by inducing cell cycle G0/G1 phase arrest in ovarian cancer cells. Additionally, USP5 knockdown inhibited xenograft growth in nude mice. Knockdown of USP5 decreased histone deacetylase 2 (HDAC2) expression and increased p27 (an important cell cycle inhibitor) expression in vitro and in vivo. The promoting effects of USP5 overexpression on cell proliferation and cell cycle transition, as well as the inhibitory effects of USP5 overexpression on p27 expression were mediated by HDAC2. Moreover, USP5 interacted with HDAC2, and disruption of USP5 enhanced the ubiquitination of HDAC2. HDAC2 protein was positively correlated USP5 protein, and negatively correlated with p27 protein in ovarian serous carcinomas tissues. Collectively, our data suggest the oncogenic function of USP5 and the potential regulatory mechanisms in ovarian carcinogenesis.


Assuntos
Carcinoma Epitelial do Ovário/enzimologia , Carcinoma Epitelial do Ovário/patologia , Endopeptidases/metabolismo , Histona Desacetilase 2/metabolismo , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/patologia , Idoso , Animais , Carcinógenos/metabolismo , Carcinoma Epitelial do Ovário/genética , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Endopeptidases/genética , Feminino , Amplificação de Genes , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Xenoenxertos , Humanos , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Neoplasias Ovarianas/genética , Prognóstico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ubiquitinação
20.
Drug Metab Dispos ; 47(12): 1388-1396, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31578206

RESUMO

Menthol, which creates mint flavor and scent, is often added to tobacco in both menthol and nonmenthol cigarettes. A potent tobacco carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), is extensively metabolized to its equally carcinogenic metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) as (R)- or (S)-NNAL enantiomers. NNAL is detoxified by UDP-glucuronosyltransferase (UGT) enzymes, with glucuronidation occurring on either NNAL's pyridine ring nitrogen (NNAL-N-Gluc) or the chiral alcohol [(R)- or (S)-NNAL-O-Gluc]. To characterize a potential effect by menthol on NNAL glucuronidation, in vitro menthol glucuronidation assays and menthol inhibition of NNAL-Gluc formation assays were performed. Additionally, NNAL and menthol glucuronides (MG) were measured in the urine of smokers (n = 100) from the Southern Community Cohort Study. UGTs 1A9, 1A10, 2A1, 2A2, 2A3, 2B4, 2B7, and 2B17 all exhibited glucuronidating activity against both l- and d-menthol. In human liver microsomes, both l- and d-menthol inhibited the formation of each NNAL-Gluc, with a stereospecific difference observed between the formation of (R)-NNAL-O-Gluc and (S)-NNAL-O-Gluc in the presence of d-menthol but not l-menthol. With the exception of three nonmenthol cigarette smokers, urinary MG was detected in all menthol and nonmenthol smokers, with l-MG comprising >98% of total urinary MG. Levels of urinary NNAL-N-Gluc were significantly (P < 0.05) lower among subjects with high levels of total urinary MG; no significant changes in free NNAL were observed. These data suggest that the presence of menthol could lead to increases in alternative, activating metabolic pathways of NNAL in tobacco target tissues, increasing the opportunity for NNAL to damage DNA and lead to the development of tobacco-related cancers. SIGNIFICANCE STATEMENT: High levels of the major menthol metabolite, menthol-glucuronide, was observed in the urine of smokers of either menthol or nonmenthol cigarettes. The fact that a significant inverse correlation was observed between the levels of urinary menthol-glucuronide and NNAL-N-glucuronide, a major detoxification metabolite of the tobacco carcinogen, NNK, suggests that menthol may inhibit clearance of this important tobacco carcinogen.


Assuntos
Carcinógenos/metabolismo , Glucuronídeos/urina , Mentol/urina , Microssomos Hepáticos/metabolismo , Nitrosaminas/metabolismo , Nitrosaminas/urina , Fumar/urina , Estudos de Coortes , Glucuronosiltransferase/genética , Glucuronosiltransferase/metabolismo , Células HEK293 , Humanos , Mentol/metabolismo , Fumar/metabolismo , Estereoisomerismo , Produtos do Tabaco , Transfecção
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