RESUMO
The Notch family of proteins plays an integral role in determining cell fates, such as proliferation, differentiation, and apoptosis. We show that Notch-1 and its ligands, Delta-like-1 and Jagged-1, are overexpressed in many glioma cell lines and primary human gliomas. Immunohistochemistry of a primary human glioma tissue array shows the presence in the nucleus of the Notch-1 intracellular domain, indicating Notch-1 activation in situ. Down-regulation of Notch-1, Delta-like-1, or Jagged-1 by RNA interference induces apoptosis and inhibits proliferation in multiple glioma cell lines. In addition, pretreatment of glioma cells with Notch-1 or Delta-like-1 small interfering RNA significantly prolongs survival in a murine orthotopic brain tumor model. These results show, for the first time, the dependence of cancer cells on a single Notch ligand; they also suggest a potential Notch juxtacrine/autocrine loop in gliomas. Notch-1 and its ligands may present novel therapeutic targets in the treatment of glioma.
Assuntos
Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Glioma/metabolismo , Glioma/patologia , Glicoproteínas/biossíntese , Proteínas de Membrana/biossíntese , Receptores de Superfície Celular/biossíntese , Fatores de Transcrição/biossíntese , Sequência de Aminoácidos , Animais , Neoplasias Encefálicas/genética , Proteínas de Ligação ao Cálcio , Processos de Crescimento Celular/fisiologia , Linhagem Celular Tumoral , Sobrevivência Celular/fisiologia , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Glioma/genética , Glicoproteínas/genética , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Proteína Jagged-1 , Ligantes , Proteínas de Membrana/genética , Camundongos , Transplante de Neoplasias , Interferência de RNA , RNA Interferente Pequeno/genética , Receptor Notch1 , Receptores de Superfície Celular/genética , Proteínas Serrate-Jagged , Fatores de Transcrição/genética , Transplante HeterólogoRESUMO
OBJECTIVE: To characterize metabolic features of women with polycystic ovary syndrome (PCOS) by exercise behavior and determine relative health benefits of different exercise intensities. DESIGN: Cross-sectional study. SETTING: Tertiary academic institution. PATIENT(S): Three hundred and twenty-six women aged 14-52 years-old with PCOS by Rotterdam criteria examined between 2006 and 2013. INTERVENTION(S): International Physical Activity Questionnaire (IPAQ) administered to classify patients into three groups based on Department of Health and Human Services (DHHS) Guidelines of vigorous, moderate, and inactive, along with physical examination and serum testing. MAIN OUTCOME MEASURE(S): Blood pressure, body mass index (BMI), waist circumference, fasting lipids, fasting glucose and insulin, 2-hour 75-gram oral glucose tolerance, homeostatic model assessment of insulin resistance (HOMA-IR). RESULT(S): The DHHS guidelines for adequate physical activity were met by 182 (56%) women. Compared with moderate exercisers and inactive women, the vigorous exercisers had lower BMI and lower HOMA-IR; higher levels of high-density lipoprotein cholesterol and sex hormone-binding globulin; and a reduced prevalence of the metabolic syndrome. In a multivariate logistic regression analysis controlling for age, BMI, and total energy expenditure, every hour of vigorous exercise reduced a patient's odds of metabolic syndrome by 22% (odds ratio 0.78; 95% confidence interval, 0.62, 0.99). CONCLUSION(S): Women with PCOS who met DHHS guidelines for exercise demonstrated superior metabolic health parameters. Vigorous but not moderate activity is associated with reduced odds of the metabolic syndrome, independent of age, BMI, and total energy expenditure. PCOS patients should be encouraged to meet activity guidelines via vigorous physical activity.