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1.
Immunity ; 42(5): 953-964, 2015 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-25992864

RESUMO

Defining specific cellular and molecular mechanisms in most obesity-related diseases remains an important challenge. Here we report a serendipitous finding that consumption of a high-fat diet (HFD) greatly increased the occurrence of skin lesions in C57BL/6 mice. We demonstrated that HFD induced the accumulation of a specific type of CD11c(+) macrophages in skin preceding detectable lesions. These cells primed skin to induce IL-1ß and IL-18 signaling, which further promoted the cytokines IFN-γ- and IL-17-mediated skin inflammation. Mechanistically, epidermal fatty acid binding protein (E-FABP) was significantly upregulated in skin of obese mice, which coupled lipid droplet formation and NLRP3 inflammasome activation. Deficiency of E-FABP in obese mice decreased recruitment of CD11c(+) macrophages in skin tissues, reduced production of IL-1ß and IL-18, and consequently dampened activation of effector T cells. Furthermore, E-FABP-deficient mice are completely resistant to HFD-induced skin lesions. Collectively, E-FABP represents a molecular sensor triggering HFD-induced skin inflammation.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Proteínas de Ligação a Ácido Graxo/metabolismo , Inflamação/etiologia , Proteínas de Neoplasias/metabolismo , Dermatopatias/imunologia , Animais , Citocinas/metabolismo , Proteínas de Ligação a Ácido Graxo/deficiência , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/imunologia , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas de Neoplasias/deficiência , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/imunologia , Dermatopatias/genética , Linfócitos T/imunologia
2.
FASEB J ; 35(4): e21264, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33715230

RESUMO

Enhanced glucose uptake is coupled with elevated aerobic glycolysis (the Warburg effect) in cancer cells and is closely correlated with increased tumor aggressiveness and poor prognosis. We previously discovered that ATM, a protein kinase deficient in Ataxia-telangiectasia (A-T) disease, is an insulin-responsive protein that participates in insulin-mediated glucose uptake in muscle cells by stimulating glucose transporter 4 (GLUT4) translocation. However, the role of ATM in glucose uptake and tumorigenesis of cancer cells is unclear. In the present study, we found that aggressive breast and prostate cancer cell lines with overactivated Akt activity exhibit enhanced glucose uptake and GLUT1 translocation upon insulin treatment, and KU-55933, a specific inhibitor of ATM, inhibits insulin-mediated glucose uptake by blocking translocation of GLUT1 to the cell surface. KU-55933 also inhibits aerobic glycolysis and ATP production in these cells. Moreover, KU-55933 induces apoptosis and inhibits motility of cancer cells by inhibiting glucose uptake. Our results showed that while high concentration of glucose and insulin promote the expression of a mesenchymal biomarker (vimentin) in these cancer cells, KU-55933 strongly inhibits its expression as well as epithelial to mesenchymal transition. The roles of ATM in stimulating glucose uptake, glycolysis, motility, and proliferation of cancer cells were demonstrated by knocking-down ATM in these cells. KU-55933 treatment also inhibits tumor growth and metastasis in vivo in mouse mammary tumors through inhibition of GLUT1 translocation and vimentin expression. These results suggest that ATM acts as a promoter of tumorigenesis in cancer cells with overactivated Akt, and KU-55933 induces apoptosis and inhibits motility by blocking GLUT1-mediated glucose uptake and glycolysis in these cancer cells, which may lead to the use of KU-55933 and its analogs as new preventive or therapeutic agents against cancer.


Assuntos
Apoptose/efeitos dos fármacos , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Glucose/metabolismo , Morfolinas/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pironas/farmacologia , Animais , Proteínas Mutadas de Ataxia Telangiectasia/genética , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Transportador de Glucose Tipo 1/genética , Humanos , Neoplasias Mamárias Experimentais/tratamento farmacológico , Camundongos , Neoplasias Experimentais/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/genética
3.
Br J Nutr ; 127(5): 641-652, 2022 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-33823947

RESUMO

Calorie restriction (CR) has been shown to be one of the most effective methods in alleviating the effects of ageing and age-related diseases. Although the protective effects of CR have been reported, the exact molecular mechanism still needs to be clarified. This study aims to determine differentially expressed (DE) miRNAs and altered gene pathways due to long-term chronic (CCR) and intermittent (ICR) CR in the brain of mice to understand the preventive roles of miRNAs resulting from long-term CR. Ten weeks old mice were enrolled into three different dietary groups; ad libitum, CCR or ICR, and fed until 82 weeks of age. miRNAs were analysed using GeneChip 4.1 microarray and the target of DE miRNAs was determined using miRNA target databases. Out of a total 3,163 analysed miRNAs, 55 of them were differentially expressed either by different CR protocols or by ageing. Brain samples from the CCR group had increased expression levels of mmu-miR-713 while decreasing expression levels of mmu-miR-184-3p and mmu-miR-351-5p compared to the other dietary groups. Also, current results indicated that CCR showed better preventive effects than that of ICR. Thus, CCR may perform its protective effects by modulating these specific miRNAs since they are shown to play roles in neurogenesis, chromatin and histone regulation. In conclusion, these three miRNAs could be potential targets for neurodegenerative and ageing-related diseases and may play important roles in the protective effects of CR in the brain.


Assuntos
Restrição Calórica , MicroRNAs , Envelhecimento/fisiologia , Animais , Encéfalo/metabolismo , Restrição Calórica/métodos , Camundongos , Camundongos Endogâmicos ICR , MicroRNAs/genética , MicroRNAs/metabolismo
4.
J Immunol ; 200(10): 3407-3419, 2018 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-29626089

RESUMO

Obesity is associated with elevated levels of free fatty acids (FAs) and proinflammatory CD11c+ macrophages. However, whether and how free FAs contribute to CD11c+ macrophage differentiation and proinflammatory functions remain unclear. Here we report that dietary saturated FAs, but not unsaturated FAs, promoted the differentiation and function of CD11c+ macrophages. Specifically, we demonstrated that stearic acid (SA) significantly induced CD11c expression in monocytes through activation of the nuclear retinoid acid receptor. More importantly, cytosolic expression of epidermal FA binding protein (E-FABP) in monocytes/macrophages was shown to be critical to the mediation of the SA-induced effect. Depletion of E-FABP not only inhibited SA-induced CD11c upregulation in macrophages in vitro but also abrogated high-saturated-fat diet-induced skin lesions in obese mouse models in vivo. Altogether, our data demonstrate a novel mechanism by which saturated FAs promote obesity-associated inflammation through inducing E-FABP/retinoid acid receptor-mediated differentiation of CD11c+ macrophages.


Assuntos
Antígeno CD11c/metabolismo , Proteínas de Ligação a Ácido Graxo/metabolismo , Inflamação/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Ácidos Esteáricos/farmacologia , Animais , Ácidos Graxos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Obesidade/metabolismo , Regulação para Cima/efeitos dos fármacos
5.
IUBMB Life ; 71(12): 1973-1985, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31424629

RESUMO

Calorie restriction (CR) is one of the most effective methods to prevent many diseases including cancer in preclinical models. However, the molecular mechanism of how CR prevents cancer is unclear. The aim of this study was to understand the role of oxidative stress (OS) in the preventive effects of different types of CR in aging mouse mammary tumor virus-transforming growth factor-alpha (MMTV-TGF-α) female mice. Mice were enrolled in ad libitum (AL), chronic CR (CCR, 15% CR) or intermittent CR [ICR, 3 weeks AL (ICR-Refeed, ICR-RF) and 1 week 60% CR (ICR-Restriction, ICR-R) in cyclic periods] groups started at the age of 10 weeks and continued until 81/82 weeks of age. Blood samples were collected to measure malondialdehyde (MDA), glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD) levels. There was no significant difference for MDA levels among the dietary groups although the chronic calorie restriction (CCR) group had lower MDA levels compared to intermittent calorie restriction (ICR) and AL group at different time points. There was also no change in MDA levels of CCR group with aging. On the other hand, the CCR group had higher CAT and SOD activity compared to ICR-R, ICR-RF, and AL groups. Moreover, GSH level was higher in CCR compared to ICR group at week 49/50 (p < .05). CAT and SOD activities were also positively correlated (p < .05). Here, for the first time, the long-term (72 weeks) effects of different types of CR on OS parameters were reported. In conclusion, moderate that is, 15%, CCR is more likely to be protective compared to the same overall calorie deficit implemented by ICR against OS that may play role in the preventive effects of CR.


Assuntos
Restrição Calórica/métodos , Eritrócitos/metabolismo , Neoplasias Mamárias Experimentais/metabolismo , Estresse Oxidativo/fisiologia , Envelhecimento/fisiologia , Animais , Antioxidantes/metabolismo , Catalase/metabolismo , Feminino , Glutationa/metabolismo , Peroxidação de Lipídeos , Malondialdeído/metabolismo , Neoplasias Mamárias Experimentais/terapia , Camundongos Endogâmicos C57BL , Superóxido Dismutase/metabolismo
6.
J Immunol ; 198(2): 798-807, 2017 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-27920274

RESUMO

Macrophages play a critical role in obesity-associated chronic inflammation and disorders. However, the molecular mechanisms underlying the response of macrophages to elevated fatty acids (FAs) and their contribution to metabolic inflammation in obesity remain to be fully elucidated. In this article, we report a new mechanism by which dietary FAs, in particular, saturated FAs (sFAs), are able to directly trigger macrophage cell death. We demonstrated that excess sFAs, but not unsaturated FAs, induced the production of cytotoxic ceramides (Cers) in macrophage cell lines. Most importantly, expression of adipose FA binding protein (A-FABP) in macrophages facilitated metabolism of excess sFAs for Cer synthesis. Inhibition or deficiency of A-FABP in macrophage cell lines decreased sFA-induced Cer production, thereby resulting in reduced cell death. Furthermore, we validated the role of A-FABP in promoting sFA-induced macrophage cell death with primary bone marrow-derived macrophages and high-fat diet-induced obese mice. Altogether, our data reveal that excess dietary sFAs may serve as direct triggers in induction of Cer production and macrophage cell death through elevated expression of A-FABP, thus establishing A-FABP as a new molecular sensor in triggering macrophage-associated sterile inflammation in obesity.


Assuntos
Ceramidas/biossíntese , Proteínas de Ligação a Ácido Graxo/metabolismo , Ácidos Graxos/efeitos adversos , Macrófagos/patologia , Animais , Western Blotting , Morte Celular , Dieta Hiperlipídica , Citometria de Fluxo , Técnicas de Silenciamento de Genes , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Confocal , Microscopia Eletrônica de Transmissão , Obesidade/metabolismo , Reação em Cadeia da Polimerase em Tempo Real
7.
Int J Mol Sci ; 18(1)2017 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-28054974

RESUMO

While translational regulation of p53 by the internal ribosome entry site (IRES) at its 5'-untranslated region following DNA damage has been widely accepted, the detailed mechanism underlying the translational control of p53 by its IRES sequence is still poorly understood. In this review, we will focus on the latest progress in identifying novel regulatory proteins of the p53 IRES and in uncovering the functional connection between defective IRES-mediated p53 translation and tumorigenesis. We will also discuss how these findings may lead to a better understanding of the process of oncogenesis and open up new avenues for cancer diagnosis and therapeutics.


Assuntos
Dano ao DNA , Regulação Neoplásica da Expressão Gênica , Sítios Internos de Entrada Ribossomal , Neoplasias/genética , Proteína Supressora de Tumor p53/genética , Regiões 5' não Traduzidas , Animais , Carcinogênese/genética , Humanos , Neoplasias/diagnóstico , Biossíntese de Proteínas , RNA Mensageiro/genética
8.
Breast Cancer Res Treat ; 158(1): 113-126, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27283835

RESUMO

Racial disparities in breast cancer incidence and outcome are a major health care challenge. Patients in the black race group more likely present with an early onset and more aggressive disease. The occurrence of high numbers of macrophages is associated with tumor progression and poor prognosis in solid malignancies. Macrophages are observed in adipose tissues surrounding dead adipocytes in "crown-like structures" (CLS). Here we investigated whether the numbers of CD163+ tumor-associated macrophages (TAMs) and/or CD163+ CLS are associated with patient survival and whether there are significant differences across blacks, non-black Latinas, and Caucasians. Our findings confirm that race is statistically significantly associated with the numbers of TAMs and CLS in breast cancer, and demonstrate that the highest numbers of CD163+ TAM/CLS are found in black breast cancer patients. Our results reveal that the density of CD206 (M2) macrophages is a significant predictor of progression-free survival univariately and is also significant after adjusting for race and for HER2, respectively. We examined whether the high numbers of TAMs detected in tumors from black women were associated with macrophage proliferation, using the Ki-67 nuclear proliferation marker. Our results reveal that TAMs actively divide when in contact with tumor cells. There is a higher ratio of proliferating macrophages in tumors from black patients. These findings suggest that interventions based on targeting TAMs may not only benefit breast cancer patients in general but also serve as an approach to remedy racial disparity resulting in better prognosis patients from minority racial groups.


Assuntos
Neoplasias da Mama/etnologia , Neoplasias da Mama/patologia , Macrófagos/imunologia , Negro ou Afro-Americano , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Neoplasias da Mama/imunologia , Proliferação de Células , Intervalo Livre de Doença , Feminino , Hispânico ou Latino , Humanos , Lectinas Tipo C/metabolismo , Macrófagos/patologia , Receptor de Manose , Lectinas de Ligação a Manose/metabolismo , Prognóstico , Receptores de Superfície Celular/metabolismo , Análise de Sobrevida , População Branca
9.
J Mammary Gland Biol Neoplasia ; 18(3-4): 333-43, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24122258

RESUMO

Overweight and/or obesity are known risk factors for postmenopausal breast cancer. More recently increased body weight has also been associated with poor prognosis for premenopausal breast cancer. This relationship has primarily been identified through epidemiological studies. Additional information from in vitro studies has also been produced in attempts to delineate mechanisms of action for the association of obesity and body weight and breast cancer. This approach has identified potential growth factors such as insulin, leptin, estrogen and IGF-I which are reported to be modulated by body weight changes. However, in vitro studies are limited in scope and frequently use non-physiological concentrations of growth factors, while long follow-up is needed for human studies. Preclinical animal models provide an intermediary approach to investigate the impact of body weight and potential growth factors on mammary/breast tumor development and progression. Here results of a number of studies addressing this issue are presented. In the majority of the studies either genetically-obese or diet-induced obese rodent models have been used to investigate spontaneous, transgenic and carcinogen-induced mammary tumor development. To study tumor progression the major focus has been allograft studies in mice with either genetic or dietary-induced obesity. In general, obesity has been demonstrated to shorten mammary tumor latency and to impact tumor pathology. However, in rodents with defects in leptin and other growth factors the impact of obesity is not as straightforward. Future studies using more physiologically relevant obesity models and clearly distinguishing diet composition from body weight effects will be important in continuing to understand the factors associated with body weight's impact on mammary/breast cancer development and progression.


Assuntos
Neoplasias da Mama/fisiopatologia , Modelos Animais de Doenças , Obesidade/fisiopatologia , Animais , Progressão da Doença , Feminino , Humanos , Camundongos
10.
Breast Cancer Res Treat ; 138(2): 395-406, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23446811

RESUMO

Previously we reported that intermittent calorie restriction (ICR) provided greater prevention of mammary tumors (MTs) than chronic calorie restriction (CCR). Here the impact of increased fat intake during refeeding in an ICR protocol was evaluated. MMTV-TGF-α female mice were assigned to one of three groups: ad libitum (AL) fed (n = 45) with free access to a moderately high fat diet (22 % fat calories); ICR (n = 45) 50 % calorie restricted for 3-week intervals followed by 3 weeks of 100 % of AL intake; and CCR (n = 45) fed 75 % of AL mice, matching each 6-week cycle of ICR mice. ICR mice were further designated as ICR-Restricted or ICR-Refed for data obtained during these intervals. All mice consumed the same absolute amount of dietary fat. Mice were followed to assess MT incidence, body weight and serum IGF-1, IGFBP3, leptin and adiponectin levels until 79 (end of final 3-week restriction) or 82 (end of final 3-weeks refeeding) weeks of age. Age of MT detection was significantly extended for CCR (74 weeks) and ICR (82 weeks) mice, compared to 57.5 weeks for AL mice. MT incidence for AL, ICR and CCR mice was 66.7, 4.4, and 52.3 %, respectively. Mammary and fat pad weights were reduced significantly following 50 % calorie restriction in ICR-Restricted mice compared to AL, CCR and ICR-Refed mice. IGF-1 and leptin levels also tended to be reduced in ICR-Restricted mice over the course of the study while adiponectin was not compared to AL, CCR, and ICR-Refed mice. The adiponectin:leptin ratio was consistently higher following 50 % restriction in ICR-Restricted mice. There was no relationship of IGF-1, leptin, or adiponectin with the presence of MTs in any groups. Thus the manner in which calories are restricted impacts the protective effect of calorie restriction independently of high fat intake.


Assuntos
Restrição Calórica , Transformação Celular Neoplásica/metabolismo , Dieta Hiperlipídica , Neoplasias Mamárias Experimentais/prevenção & controle , Adiponectina/sangue , Tecido Adiposo/patologia , Animais , Peso Corporal , Ingestão de Alimentos , Feminino , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Leptina/sangue , Neoplasias Mamárias Experimentais/sangue , Camundongos , Camundongos Transgênicos , Fator de Crescimento Transformador alfa/genética
11.
Oncol Rep ; 47(2)2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34958116

RESUMO

Mutations of p53 tumor suppressors occur more frequently in cancers at advanced stages or in more malignant cancer subtypes such as triple­negative breast cancer. Thus, restoration of p53 tumor suppressor function constitutes a valuable cancer therapeutic strategy. In the present study, it was revealed that a specific inhibitor of histone deacetylase 6, ACY­1215, caused increased acetylation of p53 in breast cancer cells with mutated p53, which was accompanied by increased expression of p21. These results suggested that ACY­1215 may lead to enhanced transcriptional activity of p53. It was also determined that ACY­1215 treatment resulted in G1 cell cycle arrest and apoptosis in these cancer cells. Furthermore, ACY­1215 displayed a synergistic effect with specific inhibitors of ATM, an activator of Akt, in inducing cancer cell apoptosis and inhibiting their motility. More importantly, it was observed that combination of ACY­1215 and ATM inhibitors exhibited markedly more potent antitumor activity than the individual compound in xenograft mouse models of breast cancer with mutant p53. Collectively, our results demonstrated that ACY­1215 is a novel chemotherapeutic agent that could restore mutant p53 function in cancer cells with strong antitumor activity, either alone or in combination with inhibitors of the ATM protein kinase.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Proliferação de Células/efeitos dos fármacos , Ácidos Hidroxâmicos/farmacologia , Neoplasias Mamárias Experimentais/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirimidinas/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Proteína Supressora de Tumor p53/metabolismo , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Modelos Animais de Doenças , Quimioterapia Combinada , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Humanos , Camundongos
12.
Cureus ; 14(8): e27895, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36120244

RESUMO

Aging and diseases related to aging, such as cancer, have been linked to oxidative stress. On the other hand, calorie restriction (CR) is one of the most effective interventions to slow down aging and prevent a variety of diseases such as cancer in preclinical models. CR has also been reported to modify oxidative stress. The aim of this study was to investigate the effects of different CR protocols and aging on oxidative stress parameters in the MMTV-TGF-α breast cancer mouse model in a cross-sectional study. Female mice were randomly enrolled in three groups: ad libitum (AL), chronic calorie restriction (CCR, 15% CR) or intermittent calorie restriction (ICR, three weeks AL followed by one week 60% CR in cyclic periods) starting at the age of 10 weeks until 81/82 weeks of age. Liver samples were analyzed for malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD), glutathione (GSH), and glutathione peroxidase (GSH-Px) levels. At week 49/50, the GSH level increased significantly in the CCR group compared to the AL and ICR-R groups which had higher mammary tumor (MT) incidence rates. Additionally, liver MDA levels in ICR groups were significantly increased, while aging led to decreased CAT and SOD activities in all CR groups. The application of different CR protocols did not have any significant effect on MDA, CAT, and SOD parameters in the liver at week 81/82. These results suggest that although GSH may interfere with MT development at the systemic level, many of the oxidative stress parameters may have more local effects on tumor development than the systemic effects.

13.
Cancer Metastasis Rev ; 29(4): 641-53, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20821253

RESUMO

It is well recognized that obesity increases the risk of various cancers, including breast malignancies in postmenopausal women. Furthermore, obesity may adversely affect tumor progression, metastasis, and overall prognosis in both pre- and postmenopausal women with breast cancer. However, the precise mechanism(s) through which obesity acts is/are still elusive and this relationship has been the subject of much investigation and speculation. Recently, adipose tissue and its associated cytokine-like proteins, adipokines, particularly leptin and adiponectin, have been investigated as mediators for the association of obesity with breast cancer. Higher circulating levels of leptin found in obese subjects could be a growth-enhancing factor as supported by in vitro and preclinical studies, whereas low adiponectin levels in obese women may be permissive for leptin's growth-promoting effects. These speculations are supported by in vitro studies which indicate that leptin promotes human breast cancer cell proliferation while adiponectin exhibits anti-proliferative actions. Further, estrogen and its receptors have a definite impact on the response of human breast cancer cell lines to leptin and adiponectin. More in-depth studies are needed to provide additional and precise links between the in vivo development of breast cancer and the balance of adiponectin and leptin.


Assuntos
Adiponectina/metabolismo , Neoplasias da Mama/metabolismo , Leptina/metabolismo , Obesidade/metabolismo , Animais , Neoplasias da Mama/patologia , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Progressão da Doença , Feminino , Humanos , Obesidade/patologia
14.
Prostate ; 71(13): 1429-40, 2011 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-21360561

RESUMO

BACKGROUND: The transgenic adenocarcinoma of mouse prostate (TRAMP) model is by far the most practical transgenic model for preclinical prostate cancer chemoprevention studies. It is critical to characterize the prostate lobe-specificity of lesion lineages to consolidate the advantages of this model and minimize its limitations for chemoprevention studies. METHODS: We dissected dorsolateral (DLP), ventral (VP), and anterior prostate (AP) lobes, and macroscopic tumors from 90 male C57BL/6J TRAMP mice at 22-24 weeks of age (WOA) and analyzed lesions by histological, biochemical and proteomic approaches. To determine whether methylseleninic acid (MSeA) led to a deletion of initiated cells, we gave oral MSeA to TRAMP mice from 5 to 23 WOA or from 5 to 15 WOA and analyzed lesions at 23 WOA. RESULTS: All tumors (n = 18) were T-antigen(+), synaptophysin (SYP)(+), androgen-receptor(-), and E-cadherin(-) poorly differentiated neuroendocrine carcinomas (NE-Ca). They were traceable most frequently to VP (66.7%) and rarely to DLP (11.1%) and AP (5.6%) with an estimated life-time incidence of 1 out of 3 mice. In DLP, epithelial lesions ranged from mild-to-severe atypical hyperplasia, with T-antigen(+), SYP(-), androgen-receptor(+), and E-cadherin(+). Proteomic profiling revealed many molecular differences between VP and DLP. In MSeA experiment, 6 out of 19 (31.5%) mice developed NE-Ca in the control group, only 2 in each MSeA group of 17-18 mice (11.1-11.8%) bore a detectable NE-Ca. CONCLUSION: The C57BL/6J TRAMP mouse represents at least two lineages of prostate carcinogenesis. Chemoprevention studies should incorporate this knowledge for efficacy assessment and molecular target validations.


Assuntos
Adenocarcinoma/prevenção & controle , Anticarcinógenos/uso terapêutico , Cisteína/análogos & derivados , Compostos Organosselênicos/uso terapêutico , Neoplasias da Próstata/prevenção & controle , Adenocarcinoma/etiologia , Adenocarcinoma/patologia , Animais , Linhagem da Célula , Cisteína/uso terapêutico , Modelos Animais de Doenças , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Metástase Neoplásica , Neoplasias da Próstata/etiologia , Neoplasias da Próstata/patologia , Proteômica , Selenocisteína/análogos & derivados , Glândulas Seminais/patologia
15.
Nutr Cancer ; 63(3): 389-401, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21462085

RESUMO

Chronic calorie restriction (CCR) prevents mammary tumor (MT) development in rodents. We reported that intermittent calorie restriction (ICR) provides greater protection than CCR in MMTV-TGF-α mice. The mammalian target of rapamycin (mTOR) pathway is involved in MT development. Here the impact of ICR versus CCR on proteins associated with mTOR signaling in mammary tissues and MTs from MMTV-TGF-α mice was determined. Mice were enrolled at 10 wk of age into ad libitum-fed (AL), CCR, and ICR groups and followed until 37/38 or 73/74 wk of age. Time points 37 and 73 followed 3 wk of 50% restriction for ICR mice, while 38 and 74 followed 1 wk of refeeding of ICR mice. Calorie restriction reduced serum IGF-I levels except for older CCR mice. At 37/38 wk, calorie restriction decreased mTOR, p70S6K, HIF-1, EGFR, and Erk protein activation and increased p4EBP1 and VEGF in mammary fat pads. At 73/74 wk, both modes of calorie restriction lowered IGF-I protein expression levels and Akt activation in MTs and mammary fat pads, and CCR increased mTOR, p70S6K, p4EBP1, and HIF-1 expression. ICR had inconsistent effects on these proteins in older mice. These results indicate that mTOR signaling proteins are modulated by age and type of calorie restriction.


Assuntos
Tecido Adiposo/patologia , Restrição Calórica , Fator de Crescimento Insulin-Like I/metabolismo , Neoplasias Mamárias Experimentais/dietoterapia , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Análise de Variância , Animais , Peso Corporal , Mama/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Ingestão de Alimentos , Ingestão de Energia , Feminino , Humanos , Fator de Crescimento Insulin-Like I/análise , Mamíferos/metabolismo , Vírus do Tumor Mamário do Camundongo/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Serina-Treonina Quinases TOR/metabolismo , Fator de Crescimento Transformador alfa/genética
16.
J Carcinog ; 10: 21, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22013391

RESUMO

Although treatments for breast cancer have improved and long-term survival after diagnosis is now common, prevention of the disease is the ultimate goal. Weight loss or weight maintenance is one approach that has been recommended to reduce the risk of breast cancer, particularly for peri/postmenopausal women. This approach is supported by decades of data indicating that calorie restriction prevents spontaneous and chemically induced mammary tumor development in rodents. In most cases, calorie restriction was implemented by a consistent daily reduction of calories, i.e. chronic calorie restriction (CCR). There have also been several studies where periods of reduced caloric intake were followed by periods of refeeding, i.e. intermittent calorie restriction (ICR), resulting in the prevention of spontaneous mammary tumorigenesis. In most of the early studies, there were no direct comparisons of CCR to ICR. One study using moderate calorie restriction in a chemically induced breast cancer rat model found a slight increase in mammary tumor incidence compared with ad libitum fed and CCR rats. However, recently, it has been demonstrated in several transgenic mouse models of breast cancer that ICR consistently provided a greater degree of protection than CCR. This review will provide a detailed comparison of ICR and CCR for breast cancer prevention. It will also examine potential mechanisms of action that may include periods of reduced IGF-I and leptin as well as an increase in the adiponectin:leptin ratio. Application of this approach to at-risk women may provide an approach to lower the risk of breast cancer in overweight/obese women.

17.
Appl Physiol Nutr Metab ; 46(8): 866-876, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33493087

RESUMO

Calorie restriction (CR) is suggested to prevent the development of mammary tumors (MTs); however, the mechanism remains to be clarified. We aimed to determine the microRNA (miRNA) profile in mice applied to 2 different CR protocols; chronic (CCR) and intermittent (ICR) and follow the MT development. In addition, the roles of miRNAs involved in adiponectin and/or leptin signaling pathways were investigated. Mice were divided into 3 groups: ad-libitum (AL), CCR, or ICR, which comprised 3 weeks of AL feeding followed by 1 week of 60% CR in a cyclic manner. Blood and tissue collection were performed at weeks 10, 17/18, 49/50 and 81/82. Long-term CCR provided better protection compared with ICR for MT development with a delay in the MT occurrence. Adiponectin expression in mammary fat pad were significantly higher in CCR group compared with AL. Using GeneChip Array, 250 of 3195 miRNAs were differentially expressed among the dietary groups. Thirteen of 250 miRNAs were related to adiponectin and/or leptin signaling genes. Results were verified by reverse transcription polymerase chain reaction. Specifically, miR-326-3p, miR-500-3p and miR-129-5p, which are related to adiponectin and/or leptin signaling, may play important roles in the preventive effects of CR in MT development and in ageing. Thus, these miRNAs might be putative biomarkers to target for diagnostic and treatment purposes. Novelty: Type of CR and micro RNA interaction is related to ageing. miR-326-3p, miR-500-3p and miR-129-5p expression levels were differentially expressed in MT development and in ageing. The genes associated with adiponectin and/or leptin signaling pathways are regulated by certain miRNAs in the protective effects of CR.


Assuntos
Adiponectina/metabolismo , Neoplasias da Mama/metabolismo , Restrição Calórica/métodos , Leptina/metabolismo , MicroRNAs/metabolismo , Transdução de Sinais , Animais , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos C57BL
18.
Cureus ; 12(1): e6737, 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-32133259

RESUMO

Leptin, an adipocytokine, is secreted from various tissues including the liver. The roles of both leptin and leptin receptor (ObR) in numerous pathophysiological conditions including mammary tumor (MT) development have been reported. However, the roles of leptin signaling-related proteins in the liver have not been reported previously in MT development. The objective of this study was to examine the expression levels of leptin and ObR in liver tissue of a transgenic breast cancer mouse model to investigate whether the roles of leptin in MT development are systemic or local. MMTV-TGF-α transgenic female mice were fed ad-libitum from week 10 up to week 74. Protein expression levels of leptin and ObR were measured in liver tissues of 74-week-old MMTV-TGF-α mice with and without MT by western blot. Serum leptin and insulin levels were measured using a enzyme-linked immunosorbent assay. Protein expression levels of leptin and ObR were similar in mice with MT compared to the ones without MT. Serum leptin and insulin levels were also not significantly different between the two groups. These results indicate that the effects of leptin signaling in MT development might be important at a local tissue level, such as mammary fat pad, and not as important at a systemic level.

19.
J Exp Clin Med (Samsun) ; 37(4): 119-125, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33408552

RESUMO

Obesity is associated with increased risk of breast cancer. Leptin is a well-known factor involved in obesity and its serum levels are increased in breast cancer. Hyperglycemia is another significant risk factor for breast cancer. Consistently, high glucose induces proliferation and invasion of breast cancer cells and in-vivo calorie restriction reduce tumorigenesis in rodent models. The aim of this study was to investigate the effect of leptin on the viability and mode of cell death in breast cancer cells incubated in different glucose concentrations to represent caloric restriction. For this purpose, MCF-7 and T47D breast cancer cells incubated in different glucose concentrations for a total of 72 hours were treated with or without leptin either for one hour or 24 hours and the ratio of apoptotic, necrotic and alive cells were analyzed by flow cytometry. Our data revealed that glucose incubation significantly decreased apoptosis and necrosis, while increasing viability in both cell lines in a dose dependent manner. One-hour leptin treatment significantly decreased viability, and increased apoptosis but did not significantly affect necrosis in T47D cells incubated in 2.5 mM glucose. In MCF-7 cells, one-hour leptin incubation significantly increased necrosis but its effects on apoptosis and viability were not significant. In conclusion, although glucose induces cell death by apoptosis and necrosis in T47D and MCF-7 cells respectively in a dose dependent manner, the overallviability is still increased in both cell lines. One-hour leptin treatment reverses the effect of low glucose incubation on apoptosis of T47D and necrosis of MCF-7 cells. Moreover, the effect of one-hour leptin treatment on apoptosis or necrosis is significantly higher than that of 24-hour leptin treatment.

20.
Prostate ; 69(3): 317-26, 2009 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-19016490

RESUMO

BACKGROUND: Previously we found that intermittent calorie restriction (ICR) delayed the age of prostate tumor detection and death in TRAMP mice in comparison to chronic calorie restricted (CCR) and ad libitum fed (AL) TRAMP mice. METHODS: In the present study the same protocol was used in a cross-sectional experiment whereby mice were either ad libitum fed, intermittently calorie restricted at 50% of the consumption of AL mice for 2 weeks followed by 2 weeks of refeeding matched to AL intake or were pair-fed to the ICR. Both ICR and CCR protocols resulted in a 25% reduction in caloric intake. Mice were enrolled in the study at 7 weeks of age to be euthanized at designated time points in cycles 3, 6, and 9 with mice euthanized at the end of restriction and refeeding. RESULTS: At the youngest time point in cycle 3 ICR impacted body weight, fat pad weights and serum factors the most. Additionally, the incidence of detectable prostate cancer pathology was reduced for ICR mice compared to AL and CCR mice. However, by cycle 5 when the mice were 28-30 weeks of age all mice except one ICR mouse had pathologically confirmed prostate cancer. Furthermore, at the two older time points many of the mice assigned to the study did not survive to reach their designated endpoints. CONCLUSIONS: Overall these findings are consistent with other studies indicating protective effects of various interventions on the development of prostate cancer in young TRAMP mice.


Assuntos
Adenocarcinoma/prevenção & controle , Adenocarcinoma/fisiopatologia , Restrição Calórica , Neoplasias da Próstata/prevenção & controle , Neoplasias da Próstata/fisiopatologia , Adenocarcinoma/patologia , Tecido Adiposo/anatomia & histologia , Fatores Etários , Animais , Peso Corporal , Estudos Transversais , Modelos Animais de Doenças , Ingestão de Alimentos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Tamanho do Órgão , Neoplasias da Próstata/patologia
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