RESUMEN
Organotropic chemopreventive effects of n-3 unsaturated fatty acids were studied using a multi-organ carcinogenesis model in male rats. Rats were treated with diethylnitrosamine (DEN), N-methyl-N-nitrosourea (MNU), N-butyl-N-4-hydroxybutylnitrosamine (BBN), 1,2-dimethylhydrazine (DMH) and dihydroxy-di-n-propylnitrosamine (DHPN) during the first 7 weeks, and then given unsaturated fatty acid (UFAs), docosahexaenoic acid (n-3, C(22:6)) (DHA), eicosapentaenoic acid (n-3, C(20:5)) (EPA), linoleic acid (n-6, C(18:2)) (LA) or oleic acid (n-9, C(18:1)) (OA) at a dose of 1.0 ml/rat, 3 times a week by gavage for the consecutive 30 weeks. All rats were fed a low LA basal diet throughout the experiment and a calorie-restricted basal diet during the period of UFAs feeding administration. DHA significantly reduced tumor size and numbers in the large intestine as compared to OA treatment. Furthermore, DHA showed a tendency to inhibit carcinogenesis in the small intestine and lung. EPA also showed a tendency to inhibit intestinal carcinogenesis. On the other hand, LA showed a tendency to inhibit lung carcinogenesis, but to promote large intestinal carcinogenesis. However these UFAs did not influence preneoplastic and neoplastic lesion development in the liver, kidney, and urinary bladder. Levels of the administered fatty acids were clearly increased in the serum and organs. In contrast, arachidonic acid (AA) levels in the large and small intestines and liver were markedly decreased by treatment with DHA and EPA. Decreased levels of AA in the large intestine correlated well with tumor incidence, although the number of glutathione S-transferase-positive (GST-P(+)) foci showed an inverse correlation with AA levels. The data thus provide evidence that an organotropism exists with regard to the influence of UFAs on carcinogenesis, which correlates with reduction of tissue AA levels in the target organs.
Asunto(s)
Carcinógenos/antagonistas & inhibidores , Carcinógenos/farmacología , Ácidos Grasos Omega-3/farmacología , Neoplasias/inducido químicamente , Neoplasias/prevención & control , Animales , Modelos Animales de Enfermedad , Ácidos Grasos Omega-3/sangre , Masculino , Neoplasias/sangre , Neoplasias/patología , Especificidad de Órganos , Ratas , Ratas Endogámicas F344RESUMEN
Insulin receptor substrate-1 (IRS-1) is one of the major substrates of insulin receptor tyrosine kinase and mediates various insulin signals downstream. In this study, we have examined the impact of three natural IRS-1 mutations identified in NIDDM patients (G971R, P170R, and M209T) on insulin signaling. G971R is located near src homology 2 protein binding sites, and P170R and M209T are located in the phosphotyrosine binding domain of IRS-1. 32D-IR cells, stably overexpressing human insulin receptor, were transfected with wild-type human IRS-1 cDNA (WT) or three mutant IRS-1 cDNAs and analyzed. All the cell lines expressing mutant IRS-1 showed a significant reduction in [3H]thymidine incorporation compared with WT. Upon insulin stimulation, cells expressing G971R showed a 39% decrease (P < 0.005) in phosphatidylinositol 3-kinase (PI 3-kinase) activity, a 43% decrease (P < 0.01) in binding of the 85-kDa regulatory subunit of PI 3-kinase, and a 22% decrease (P < 0.05) in mitogen-activated protein kinase activity compared with those expressing WT. Cells expressing P170R and M209T showed slight but significant decreases in PI 3-kinase activity (17 and 14%, respectively; both P < 0.05) and in binding of p85 (22 and 16%, respectively; both P < 0.05) and a greater decrease in mitogen-activated protein kinase activity (41 and 43%, respectively; both P < 0.005) compared with WT. After insulin stimulation, cells expressing P170R and M209T showed significant decreases in IRS-1 phosphorylation (37 and 42%, respectively; both P < 0.05) and in IRS-1 binding to the insulin receptor (48 and 53%, respectively; P < 0.01) compared with WT. G971R showed no changes in IRS-1 phosphorylation and in IRS-1 binding to the insulin receptor compared with WT. These data suggest that the impaired mitogenic response of P170R and M209T was mainly due to reduced binding to the insulin receptor, whereas the impaired response of G971R was mainly due to reduced association with PI 3-kinase p85.
Asunto(s)
Regulación de la Expresión Génica/genética , Insulina/farmacología , Mutación/genética , Fosfoproteínas/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Receptor de Insulina/metabolismo , Transducción de Señal , Animales , Western Blotting , Proteínas Quinasas Dependientes de Calcio-Calmodulina/metabolismo , Línea Celular , ADN/biosíntesis , ADN Complementario/genética , Electroforesis en Gel de Poliacrilamida , Activación Enzimática , Humanos , Proteínas Sustrato del Receptor de Insulina , Ratones , Fosfoproteínas/biosíntesis , Fosfoproteínas/metabolismo , Fosforilación , Pruebas de Precipitina , Ratas , Timidina/metabolismoRESUMEN
Selenium concentrations in whole blood of Japanese and American women with and without breast cancer and benign fibrocystic breast disease were determined. The observed blood Se levels of healthy Japanese women (0.286 +/- 0.021 micrograms/ml) were similar to previously reported values for healthy Japanese adults. The Japanese patients with benign breast disease and with breast cancer exhibited blood selenium concentrations of 0.200 +/- 0.045 and 0.195 +/- 0.057 micrograms/ml, respectively. The mean blood Se concentration of Japanese breast cancer patients with recurrence was 0.188 +/- 0.061 micrograms/ml. The mean blood Se concentrations of healthy American women from San Diego, Calif., were 0.191 +/- 0.023 micrograms/ml; of women with benign fibrocystic disease, 0.142 +/- 0.010 micrograms/ml; and of breast cancer patients, 0.167 +/- 0.032 micrograms/ml. The higher blood Se concentrations of Japanese healthy subjects as compared to healthy Americans can be attributed to differences in the dietary Se intakes; low blood Se concentration may be indicative of increased breast cancer risk.