Nutrition and cancer: metabolomic, and proteomic profile of muscle, placental, fetal, and tumor cell signaling pathways in Walker-256 tumour-bearing pregnant rats submitted to leucine nutritional supplementation

• Grant number: 14/13334-7
• Support Opportunities: Regular Research Grants
• Start date: March 01, 2016
• End date: February 28, 2018
• 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: Bread Leandro Gomes da Cruz ; Emilianne Miguel Salomão

Abstract

In our laboratory, we have as main objective the elucidation of metabolic and molecular effects of the cachectic state induced by tumour growth. Cancer-cachexia is considered a major problem in the treatment of solid tumours, especially pancreatic, stomach, lung and colon cancer, since these patients have intensive mobilization of host tissues, preferably depleting the skeletal muscle protein due to increased degradation and / or decreased protein synthesis in muscle. In contrast, pregnancy is characterized by maternal physiological changes, primarily correlated to hormones profile, especially oestrogen, progesterone, prolactin and hCG, essential to support foetal growth. Literature data report that the pregnancy hormones have influenced and modulated the risk and growth of breast cancer. Therefore, this proposal aims to investigate the effects of tumour growth, Walker-256 carcinoma and MAC16 colon adenocarcinoma, experimental models of cachexia, on the host spoliation and especially the mechanisms involved on protein catabolism and inhibition of muscle protein synthesis. Currently, we have a major interest to elucidate the mechanism of tissue catabolism induced by proteolysis-inducing (PIF) or Factor Walker (FW) factor, investigating the action mechanism of second messenger activated by PIF and FW in vitro in skeletal muscle cells (C2C12), fibroblast cells (Vero cells) and also trophoblastic cells (BeWo cells), and in vivo assays, assessing the activation of proteasome system and increased protein degradation, as well as the processes of protein synthesis inhibition in these processes associated with nutritional supplementation with leucine. This branched-chain amino acid acts as the structural element for the processes of protein synthesis and also is used as an energy source by skeletal muscle, and also leads the cell signalling process, preserving body protein mass. Thus, the main objective of this work is to evaluate how nutritional supplementation with leucine associated with the influence of pregnancy hormones can influence and modulate mainly the effects of Walker 256 tumour growth of in vitro and in vivo. Female Wistar rats will be distributed in eight different groups, such as: control (C), Walker-256 tumour-bearing (W), pregnant (P) and pregnant, tumour bearing (PW); and four groups fed with a leucine-rich diet: control leucine (L), tumour-bearing leucine (LW), pregnant fed leucine-rich diet (LP); pregnant tumour-bearing fed leucine-rich diet (LPW). After 19 days of experiment, the animals will be sacrificed for analysis of metabolomic profile, concentrations of hormones and cytokines in serum and the muscle, placenta, foetal and tumour tissues metabolomic and proteomics profiles, protein expression related to synthesis and degradation processes will be analysed and also the cell signalling, proliferation and apoptosis. In in vitro experiments, the Walker-256 tumour cells established in culture will be treated with pregnancy hormones and evaluate the proliferation and cytotoxicity on these cells and also the effects on cell signalling proteins and apoptosis. (AU)

Scientific publications

(11)

(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 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)

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)

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)

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)

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)

OLIVEIRA, ANDRE G.; GOMES-MARCONDES, MARIA CRISTINA C.. Metformin treatment modulates the tumour-induced wasting effects in muscle protein metabolism minimising the cachexia in tumour-bearing rats. BMC CANCER, v. 16, JUL 7 2016. (08/07737-0, 14/13334-7, 13/16115-1, 10/00209-9)

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)

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)