Nutrition and cancer: metabolomic and proteomic profile of muscle and tumor cell signaling pathways in vivo and in vitro assays under leucine nutritional supplementation

• Grant number: 15/06766-0
• Support Opportunities: Scholarships in Brazil - Post-Doctorate
• Effective date (Start): November 01, 2015
• Effective date (End): October 31, 2018
• Field of knowledge: Biological Sciences - Physiology
• Principal Investigator: Maria Cristina Cintra Gomes Marcondes
• Grantee: Bread Leandro Gomes da Cruz
• 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

Cancer is the second cause of death worldwide and the cachexia caused by some types of tumor is largely responsible for it. Cancer-cachexia is more prevalent in gastrointestinal tumors, lung, pancreatic, breast and thyroid, being characterized by the unintentional weight loss, mainly wasting the lean body mass. Studies are efforted to maintain lean body mass in cachectic host, being important to contribute to the reduction of deaths and preserve the quality of life in these patients. In recent studies, leucine has been shown to be effective in maintaining lean body mass by stimulating muscle protein synthesis and inhibiting the protein degradation, especially in skeletal muscle mass. Therefore, to better understanding more studies are needed to investigate how the presence of leucine stimulates protein synthesis and protect the host waste in the cachectic state. In our previous works, we search, as main objective, the elucidation of metabolic and molecular effects of the cachectic state. Cancer-cachexia is considered a major problem in the treatment of solid tumors mainly because of the intensive mobilization of host's substrates, preferably depletion of muscle protein as a result of the increase of degradation and/or reduced protein synthesis in muscle. Thus, we aim to investigate the effects of Walker tumor growth as an experimental model of cachexia. Currently our main interest is to elucidate the mechanism of tissue catabolism induced by proteolysis-inducing factor (PIF) or Factor Walker (FW), assessing the activation of the ubiquitin-proteosomal protein degradation pathway, as well as methods of stimulating the protein synthesis via under the nutritional supplementation with leucine, knowing that this amino acid also acts as cell signaling, thereby preserving the body protein mass. Thus, we intent to evaluate how nutritional supplementation with leucine can influence and mainly modulate the Walker-256 tumour (W) growth effects in vitro and in vivo. Therefore, in vivo studies will be conducted in rats, distributed into four different groups, namely: control (C), tumor bearing rats (W), subjected to leucine-rich diet (L) and subjected to leucine-rich diet and tumor-bearing (LW). After inoculation of Walker-256 tumour, animals will be sacrificed on the seventh, fourteenth and twenty-first days in order to evaluate the tumour time course effects. Serum and tissues (tumour and muscle) samples will be collected for metabolomic profile analysis, hormones and cytokines concentrations in serum and muscle and tumor tissue will be assassed to metabolomic profiles, proteomic, protein expression related to signaling processes for cell proliferation and apoptosis. The in vitro experiments, assessed in myotubules, C2C12 cells established in culture, will be treated with leucine solution and Walker factor (FW). The proliferation of these cells and the cytotoxicity will be evaluated in addition to the effects on signaling proteins in cell proliferation and apoptosis. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

CRUZ, BREAD; OLIVEIRA, ANDRE; CINTRA GOMES-MARCONDES, MARIA CRISTINA. L-leucine dietary supplementation modulates muscle protein degradation and increases pro-inflammatory cytokines in tumour-bearing rats. CYTOKINE, v. 96, p. 253-260, AUG 2017. (15/06766-0, 11/08276-0, 14/13334-7, 13/16115-1)

CRUZ, BREAD; OLIVEIRA, ANDRE; VIANA, LAIS ROSA; LOPES-AGUIAR, LEISA; CANEVAROLO, RAFAEL; COLOMBERA, MAIARA CAROLINE; VALENTIM, RAFAEL ROSSI; GARCIA-FOSSA, FERNANDA; DE SOUSA, LIZANDRA MAIA; CASTELUCCI, BIANCA GAZIERI; et al. Leucine-Rich Diet Modulates the Metabolomic and Proteomic Profile of Skeletal Muscle during Cancer Cachexia. CANCERS, v. 12, n. 7, JUL 2020. (15/06766-0, 17/02739-4)

CRUZ, BREAD; OLIVEIRA, ANDRE; VENTRUCCI, GISLAINE; CINTRA GOMES-MARCONDES, MARIA CRISTINA. A leucine-rich diet modulates the mTOR cell signalling pathway in the gastrocnemius muscle under different Walker-256 tumour growth conditions. BMC CANCER, v. 19, APR 11 2019. (13/16115-1, 15/06766-0, 17/02739-4)