Nutrition and Câncer. Molecular, Proteomic and Metabolomic aspects in experimental model of cachexia.

Abstract

In our previous works related to cancer and cachexia, the main objectives are to elucidate the metabolic and molecular changes that occurred during the development of the cachectic cancer state. Cachexia imposed by cancer, is considered a significant problem in the treatment of solid tumours, especially pancreatic, stomach, lung and colon since these patients by intensive mobilization of substrates of the body casing fabrics, there are preferably depletion of muscle protein due to the increase of degradation and/or reduced protein synthesis in muscle. Moreover, patients with cachexia have a very short life expectancy and consequently lower quality of life higher the degree of weight loss, that seems to be mediated by reduced food intake, but by catabolic factor produced by the tumour. Moreover, clinical complications that can occur during pregnancy are more complex because of the coexistence between two metabolic conditions, such as foetal growth and tumour development. Therefore, the knowledge of the molecular, biochemical, proteomic and metabolomic mechanisms during cachexia could be used for the clinical treatment and, more importantly, could be focused on the time-course profile conducting to the knowledge of the start and intensity of cachexia state. Thus, our work of research (until then supported by FAPESP) aimed to investigate the mechanisms involved in protein catabolism and inhibition of muscle protein synthesis under the effects of Walker tumour growth and MAC16 colon adenocarcinoma, considered experimental models of cachexia. Currently, we aim to elucidate the mechanism of tissue protein turnover in vivo, assessing the activation of the proteasomal system, as well as the inhibition of protein synthesis involved in these two experimental models of cachexia, assessing the biochemical and molecular processes of cell signalling and also the metabolomic and proteomic profiles. In addition, we will evaluate the dietary supplementation with branched-chain amino acids, particularly leucine, and its beneficial effects on the skeletal muscle of tumour-bearing animals, thus preserving the body protein mass. Our particular interest is the investigation of cell signalling processes involved in synthesis and catabolism processes combined with nutritional supplementation leucine. This thematic project should join all sub-projects developed in our laboratory. The main area is nutrition and cancer associated with pregnancy status, development and physical activity in which all these themes are associated with tumour development and all the studies have great importance as the basic knowledge and also to the possibility of translation to the clinic treatment. The main objective was to study the biochemical and molecular mechanisms involved in protein metabolism of the host, focusing different tissues as placenta, foetus organism, host tissues as muscle, liver, and heart in tumour-bearing animals with Walker tumour or MAC16 colon adenocarcinoma, submitted or not to leucine-rich diet. On the other hand, in the our Laboratory, we isolated and purified protein with approximate molecular weight of 24kDa from the ascitic fluid of the Walker 256 tumour-bearing rats, named Factor Walker (FW), and this glycoprotein similar to proteolysis-inducing factor (PIF), has similar deleterious effects in vitro, encouraging us to study this factor in different cell types. Thus this work will also study the molecular and biochemical mechanisms involved in protein synthesis and degradation metabolism and also the metabolomic profile of the effects produced by FW and also PIF modulated by branched-chain amino acid, leucine in skeletal muscle cells (C2C12 cells differentiated in myotubes), fibroblast cells (strain Vero) and trophoblast cells (BeWo lineage) in culture.