Nutrition and cancer: study of molecular, proteomic and metabolomic aspects of experimental model of cachexia

• Grant number: 17/02739-4
• Support Opportunities: Research Projects - Thematic Grants
• Start date: July 01, 2017
• End date: June 30, 2024
• Field of knowledge: Health Sciences - Nutrition - Malnutrition and Physiological Development
• Principal Investigator: Maria Cristina Cintra Gomes Marcondes
• Grantee: Maria Cristina Cintra Gomes Marcondes
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated researchers: André Gustavo de Oliveira ; Bread Leandro Gomes da Cruz ; Laís Rosa Viana ; Luiz Alberto Ferreira Ramos
• Associated scholarship(s): 23/12635-2 - In vitro study of the effect of supplementation with leucine and aqueous extract of acerola (Malpighia emarginata DC.) in modulating the effects of cancer cachexia, BP.IC; 22/10248-9 - Nutraceutics in the pathological condition of cachetic rats: effects of supplementation with leucine and lyophilised extract of acerola on tumour and muscle tissue responses, BP.DR; 23/01743-9 - Cardiotoxic effects of chemotherapy treatment with doxorubicin and cyclophosphamide and the possible benefits of nutritional supplementation with leucine in pregnant Wistar rats with the Walker 256 tumor., BP.IC; + associated scholarships 23/01811-4 - Evaluation of placental oxidative and glycolytic metabolism of pregnant Wistar rats Walker 256 tumour-bearing and treated with Doxorubicin chemotherapy and Cyclophosphamide, BP.MS; 22/13789-0 - Nutrition and Cancer. Study of molecular, proteomic and metabolomic aspects in an experimental model of cachexia, BP.TT; 22/06594-9 - Nutrition and Cancer: study of molecular, proteomic and metabolomic aspects in an experimental model of cachexia, BP.PD; 22/02114-2 - Evaluation of the placental proteomic profile in rats with Walker 256 tumor and under a leucine-rich diet intervention, BP.IC; 21/08188-5 - In vitro and in vivo effects of treatment with leucine, progesterone, sitagliptin and liraglutide on inflammatory and cell proliferation pathways mechanisms in placentas exposed to cyclophosphamide and doxorubicin chemotherapy, BP.DR; 21/13840-3 - Nutrition and Cancer. Study of molecular, proteomic and metabolomic aspects in an experimental model of cachexia, BP.TT; 20/13222-5 - Evaluation of leucine supplementation on the tumor factors effects in H9c2 cardiac cells, BP.MS; 19/20558-2 - Nutrition and Câncer. Molecular, Proteomic and Metabolomic aspects in experimental model of cachexia., BP.PD; 19/19779-4 - Modulatory effect of leucine in H9c2 cardiomioblasts under Walker-256 tumor factors, BP.IC; 19/13937-7 - Nutrition and Câncer. Molecular, Proteomic and Metabolomic aspects in experimental model of cachexia., BP.PD; 19/14803-4 - Nutrition and Câncer. Molecular, Proteomic and Metabolomic aspects in experimental model of cachexia., BP.PD; 18/20637-7 - Evaluation of the effects of nutritional supplementation with leucine on the placental activity of Walker 256 tumour-bearing rats during pregnancy evolution, BP.MS; 17/23065-1 - Nutrition and cancer: study of molecular, proteomic and metabolomic aspects of experimental model of cachexia, BP.PD; 15/21890-0 - Effect of leucine, ketogenic and combined diets in tumor growth, cachectic state and metabolomic systemic profile, muscle and tumor in rats with cancer cachexia (Walker 256 model), BP.PD; 15/06766-0 - Nutrition and cancer: metabolomic and proteomic profile of muscle and tumor cell signaling pathways in vivo and in vitro assays under leucine nutritional supplementation, BP.PD - associated scholarships

Abstract

In our previous works related to cancer and Cachexia the main objectives are to elucidate 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 tumors, 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 very short life expectancy and consequent lower quality of life greater 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 fetal 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 important, 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 proteosomal 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 signaling 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 signaling 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 a 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, fetus 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. (AU)

Scientific publications

(15)

(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)

DA SILVA MIYAGUTI, NATALIA ANGELO; PEREIRA DE OLIVEIRA, SARAH CHRISTINE; CINTRA GOMES-MARCONDES, MARIA CRISTINA. Maternal nutritional supplementation with fish oil and/or leucine improves hepatic function and antioxidant defenses, and minimizes cachexia indexes in Walker-256 tumor-bearing rats offspring. Nutrition Research, v. 51, p. 29-39, MAR 2018. (17/02739-4, 14/13334-7, 13/16115-1, 15/09371-7)

DE MATUOKA E CHIOCCHETTI, GABRIELA; LOPES-AGUIAR, LEISA; DA SILVA MIYAGUTI, NATALIA ANGELO; VIANA, LAIS ROSA; SALGADO, CARLA DE MORAES; ORVOEN, OPHELIE OCEAN; FLORINDO, DERLY; DOS SANTOS, ROGERIO WILLIAMS; CINTRA GOMES-MARCONDES, MARIA CRISTINA. A Time-Course Comparison of Skeletal Muscle Metabolomic Alterations in Walker-256 Tumour-Bearing Rats at Different Stages of Life. METABOLITES, v. 11, n. 6, JUN 2021. (17/02739-4, 15/21890-0, 18/20637-7, 19/14803-4, 19/13937-7, 19/20558-2)

MIYAGUTI, NATALIA ANGELO DA SILVA; CHIOCCHETTI, GABRIELA DE MATUOKA E; SALGADO, CARLA DE MORAES; LOPES-AGUIAR, LEISA; VIANA, LAIS ROSA; BLANCHARD, LEA; DOS SANTOS, ROGERIO WILLIANS; GOMES-MARCONDES, MARIA CRISTINA CINTRA. Walker-256 Tumour-Induced Cachexia Altered Liver Metabolomic Profile and Function in Weanling and Adult Rats. METABOLITES, v. 11, n. 12, DEC 2021. (19/14803-4, 19/20558-2, 19/13937-7, 15/21890-0, 17/02739-4, 18/20637-7)

FAVERO-SANTOS, BIANCA CRISTINE; CINTRA GOMES-MARCONDES, MARIA CRISTINA. Leucine can modulate the expression of proteins related to protein degradation signalling under mTOR inhibition in C2C12 cells. Cellular & Molecular Biology, v. 64, n. 10, p. 73-78, 2018. (13/16115-1, 17/02739-4, 14/13334-7)

OLIVEIRA, MELINA DE MORAES SANTOS; SALGADO, CARLA DE MORAES; VIANA, LAIS ROSA; GOMES-MARCONDES, MARIA CRISTINA CINTRA. Pregnancy and Cancer: Cellular Biology and Mechanisms Affecting the Placenta. CANCERS, v. 13, n. 7, APR 2021. (18/20637-7, 17/02739-4, 15/21890-0)

TOMASIN, REBEKA; RHEDER FAGUNDES PASCOAL, AISLAN CRISTINA; SALVADOR, MARCOS JOSE; CINTRA GOMES-MARCONDES, MARIA CRISTINA. Aloe veraand Honey Solution and Their Ethanolic Extraction Solution Could Act on Metastasis-Regulating Processes in Walker 256 Tumor Tissues In Vivo?. NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL, v. 73, n. 7, JUN 2020. (10/00714-5, 10/00209-9, 14/13334-7, 17/02739-4, 11/17067-5, 15/03726-8)

DA SILVA MIYAGUTI, NATALIA ANGELO; STANISIC, DANIJELA; PEREIRA DE OLIVEIRA, SARAH CHRISTINE; DOS SANTOS, GABRIELA SALES; MANHE, BEATRIZ SCHINCARIOL; TASIC, LJUBICA; CINTRA GOMES-MARCONDES, MARIA CRISTINA. Serum and Muscle(1)H NMR-Based Metabolomics Profiles Reveal Metabolic Changes Influenced by a Maternal Leucine-Rich Diet in Tumor-Bearing Adult Offspring Rats. NUTRIENTS, v. 12, n. 7, JUL 2020. (19/13937-7, 17/10809-2, 17/02739-4, 14/13334-7)

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)

DE QUADROS, V. P.; TOBAR, N.; VIANA, L. R.; DOS SANTOS, R. W.; KIYATAKA, P. H. M.; GOMES-MARCONDES, M. C. C.. The 17 beta-oestradiol treatment minimizes the adverse effects of protein restriction on bone parameters in ovariectomized Wistar rats RELEVANCE TO OSTEOPOROSIS AND THE MENOPAUSE. BONE & JOINT RESEARCH, v. 8, n. 12, p. 573-581, DEC 2019. (15/21890-0, 17/02739-4, 14/13334-7)

VIANA, LAIS ROSA; TOBAR, NATALIA; BRANDT BUSANELLO, ESTELA NATACHA; MARQUES, ANA CAROLINA; DE OLIVEIRA, ANDRE GUSTAVO; LIMA, TANES I.; MACHADO, GABRIELLY; CASTELUCCI, BIANCA GAZIERI; RAMOS, CELSO DARIO; BRUNETTO, SERGIO Q.; et al. Leucine-rich diet induces a shift in tumour metabolism from glycolytic towards oxidative phosphorylation, reducing glucose consumption and metastasis in Walker-256 tumour-bearing rats. SCIENTIFIC REPORTS, v. 9, OCT 29 2019. (15/21890-0, 12/06955-0, 17/02739-4, 14/13334-7)

OLIVEIRA, SARAH CHRISTINE PEREIRA DE; MIYAGUTI, NATALIA ANGELO DA SILVA; RUSSELL, STEVEN THOMAS; TOBAR, NATALIA; GERALDO, MURILO VIEIRA; GOMES-MARCONDES, MARIA CRISTINA CINTRA. Fish Oil Diet during Pre-mating, Gestation, and Lactation in Adult Offspring Rats on Cancer Cachexia Prevention. MOLECULAR NUTRITION & FOOD RESEARCH, v. 65, n. 9, APR 2021. (17/10809-2, 18/11932-5, 19/13937-7, 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)

DA SILVA MIYAGUTI, NATALIA ANGELO; PEREIRA DE OLIVEIRA, SARAH CHRISTINE; CINTRA GOMES-MARCONDES, MARIA CRISTINA. Maternal Leucine-Rich Diet Minimises Muscle Mass Loss in Tumour-bearing Adult Rat Offspring by Improving the Balance of Muscle Protein Synthesis and Degradation. BIOMOLECULES, v. 9, n. 6, JUN 2019. (17/10809-2, 17/02739-4, 14/13334-7)

VIANA, LAIS ROSA; LOPES-AGUIAR, LEISA; ROSOLEN, RAFAELA ROSSI; DOS SANTOS, ROGERIO WILLIANS; CINTRA GOMES-MARCONDES, MARIA CRISTINA. H-1-NMR Based Serum Metabolomics Identifies Different Profile between Sarcopenia and Cancer Cachexia in Ageing Walker 256 Tumour-Bearing Rats. METABOLITES, v. 10, n. 4, APR 2020. (15/21890-0, 12/06955-0, 17/02739-4, 14/13334-7, 19/20558-2)

VIANA, LAIS ROSA; TOBAR, NATALIA; BUSANELLO, ESTELA; MARQUES, ANA CAROLINA; LIMA, TANES; MACHADO, GABRIELLY; CASTELUCCI, BIANCA; RAMOS, CELSO DARIO; SERGIO; SILVEIRA, LEONARDO REIS; et al. Leucine-rich diet changes tumor metabolism, reducing glucose consumption and metastasis in Walker 256 tumor-bearing rats. FASEB JOURNAL, v. 33, p. 2-pg., 2019-04-01. (12/06955-0, 15/21890-0, 17/02739-4, 14/13334-7)