RESUMO
Isoprenylcysteine carboxylmethyltransferase (ICMT) catalyzes the post-translational modification of RAB GTPases that contain C-terminal CXC motifs. However, the functional impact of this modification on RAB proteins has not been actively explored. We found that inhibition of ICMT significantly reduced cell migration in vitro and cancer invasion and metastasis in vivo. This role of ICMT was found to be mediated by RAB4A, an essential regulator of the fast recycling of integrin ß3. Integrin ß3 regulates cell polarity and migration when localized appropriately to the plasma membrane, thereby having an essential role in cancer metastasis. ICMT catalyzed carboxylmethylation is critical for RAB4A activation and interaction with effectors, its localization to endosomes and recycling vesicles, and hence important for RAB4A-dependent integrin ß3 recycling to plasma membrane. These findings bring attention to the effects of C-terminal carboxylmethylation on RAB GTPases and provide a rationale for targeting ICMT in the treatment of metastatic cancer.
Assuntos
Integrina beta3/genética , Neoplasias/genética , Proteínas Metiltransferases/genética , Proteínas rab4 de Ligação ao GTP/genética , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Polaridade Celular , Galinhas , Endossomos/enzimologia , Humanos , Integrina beta3/metabolismo , Camundongos , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Metástase Neoplásica , Neoplasias/fisiopatologia , Proteínas Metiltransferases/metabolismo , Processamento de Proteína Pós-Traducional , Proteínas rab4 de Ligação ao GTP/metabolismoRESUMO
In two surveys in The Peoples Republic of China, blood samples were collected for nutritional studies in two counties where the risks of esophageal cancer are very different. The first survey was done in May 1980 in Linxian County (Henan Province) where the risk of esophageal cancer is very high. Blood samples were obtained from 111 persons (58 men, 53 women) who were selected randomly from 528 subjects that underwent endoscopical examination. The second survey was done in May 1981 in Jiaoxian County (Shandong Province) where the risk of esophageal cancer is reported to be relatively low. Blood samples were obtained from 120 persons (66 men, 54 women) who were selected randomly from 252 subjects that had also had undergone endoscopy. The blood samples were used to measure the nutritional status of riboflavin (erythrocyte glutathione reductase activation coefficient), vitamin A (retinol and carotene concentrations), and zinc (plasma and hair zinc concentrations). Only riboflavin status was significantly different in the two communities. The distribution of erythrocyte glutathione reductase activation coefficient values suggested that riboflavin status was much better in the low-risk community. Also in May 1981, a few more blood samples were obtained from some of the participants of the previous year's study in Linxian. A slight improvement in riboflavin and zinc status was detected. We considered the possibility that these changes may have been linked to the socioeconomic changes currently taking place in rural areas. Data were also collected from food allocation records in 15 production brigades in Linxian and 13 production brigades in Jiaoxian in the same years. The records used represented the food consumption of 3,491 and 2,552 persons, respectively, and were used to calculate daily food and nutrient intakes in the two communities. Dietary analyses highlighted the vegetarian nature of the diet, the low consumption of riboflavin, and the virtual dependence on carotene for vitamin A. Both communities consumed very little in the way of animal products or fruit, but intake of these items was higher in Jiaoxian.