Nutrition and Cancer: study of molecular, proteomic and metabolomic aspects in an experimental model of cachexia

• Grant number: 22/06594-9
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: June 01, 2022
• End date: May 31, 2023
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Maria Cristina Cintra Gomes Marcondes
• Grantee: Guilherme Augusto da Silva Nogueira
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 17/02739-4 - Nutrition and cancer: study of molecular, proteomic and metabolomic aspects of experimental model of cachexia, AP.TEM

Abstract

In our previous results related to Cancer and cachexia studied the metabolic and molecular changes occurred during the development of the Cancer cachectic state. Cachexia imposed by Cancer, is considered a major problem in the treatment of solid tumours, especially pancreatic, stomach, lung and colon since these patients have an intensive substrate mobilization from host body tissues, since the depletion of muscle protein is mainly occurred by increasing degradation and/or reducing protein synthesis processes. Moreover, patients with cachexia have very short life expectancy and consequent lower quality of life, due to the greater weight loss, that seems to be mediated by reduced food intake, and also by catabolic factor produced by the tumour. In addition, clinical complications during pregnancy are even more complex during Cancer evolution, because of the coexistence of two metabolic conditions such as foetal growth and tumour development. Therefore, the knowledge of the molecular, proteomic and metabolomic via during cachexia associated with pregnancy could be useful for clinical treatment and, more important, could be focused on the time-course profile conducting to the knowledge of the onset and the intensity of cachexia state. In our previous works related to Cancer-cachexia associated with leucine nutritional supplementation showed beneficial effects in skeletal muscle of tumour-bearing animals. Thus, our work 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 ubiquitin-proteasome 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 these studies have a great importance as the basic knowledge and also because have a great 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, and 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 our Laboratory, we have isolated and purified a 24kDa protein from the ascitic fluid of the Walker 256 tumour-bearing rats, named Factor Walker (WF), which has a similar molecular weight as the glycoprotein proteolysis-inducing factor (PIF). The WF 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. (AU)