Study of molecular targets important for the control of cancer metabolism - the mTOR/S6K pathway as a central role

• Grant number: 18/14818-9
• Support Opportunities: Research Grants - Young Investigators Grants - Phase 2
• Start date: May 01, 2019
• End date: April 30, 2025
• Field of knowledge: Health Sciences - Nutrition - Nutrition Biochemistry
• Principal Investigator: Fernando Moreira Simabuco
• Grantee: Fernando Moreira Simabuco
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• City of the host institution: São Paulo
• Associated researchers: Augusto Ducati Luchessi ; Carlos Frederico Martins Menck ; Clarissa Ribeiro Reily Rocha ; Isadora Carolina Betim Pavan ; Maurício Ariel Rostagno ; Roger Chammas ; Rosângela Maria Neves Bezerra ; Tharcisio Citrangulo Tortelli Junior
• Associated research grant: 12/13558-7 - Molecular characterization of S6Ks in obesity and its associated diseases., AP.JP
• Associated research grant(s): 20/05346-6 - Interaction studies between cellular proteins and viral proteins of the new coronavirus 2019 (SARS-CoV-2), AP.R
• Associated scholarship(s): 22/12230-0 - Analysis of the effectiveness of co-treatment of PARP1 inhibitors with S6Ks inhibitors as a therapeutic strategy against breast cancer cells, BP.IC; 20/13660-2 - Genome editing of LKB1 gene by CRISPR/Cas9 in lung cancer cells and evaluation of its role in metformin and cisplatin response., BP.MS; 20/08684-0 - Study of the interaction between PARP1 and S6K2 and its relation with cancer metabolism and DNA repair, BP.DD; + associated scholarships 20/09133-7 - Genome wide analysis of cisplatin resistance associated genes in A549 lung cancer cells using a CRISPR/Cas9 library., BP.PD; 19/25582-9 - Study of the role of NRF2 protein in metabolism regulation and redox control in response to natural food-derived compounds in prostate cancer cells, BP.DD; 19/25731-4 - Characterization of the soluble isoform of FAS protein (CD95) on cisplatin and apoptosis resistance in lung cancer cells using CRISPR technology, BP.IC; 19/13848-4 - Evaluation of natural compounds from beetroot against cervical cancer cells HeLa, BP.IC - associated scholarships

Abstract

Despite diagnostic and therapeutic advances in the last decades, cancer is still one of the deadliest diseases around the world. The lack of a cure for cancer reflects the complexity of its molecular bases, where the deregulation of cellular metabolic pathways is considered one of the emerging hallmarks of the disease. Therefore, there is currently a great demand for a better understanding of the molecular targets and mechanisms related to metabolism in cancer, which may have important roles in cancer progression, resistance and may be aimed for therapy. The mTOR/S6Ks pathway is related to the control of cell growth in response to nutrients, growth factors and cellular energy balance and has been associated with cancer progression and alterations in cancer metabolism. In this project we aim to study important molecular targets related to the mTOR/S6Ks pathway and metabolism control in cancer, amongst them, LKB1, NRF2 and PARP1. LKB1 is an important upstream regulator of the mTOR pathway often mutated in cancer, NRF2, related to oxidative stress, has a dual described relationship with mTOR and cancer and PARP1 has recently been detected as an interacting partner of S6Ks by our group. We intend in this project to genetically alter the expression of those target genes and evaluate effects on cancer metabolism, redox control, DNA repair and the responsiveness of cancer cells to food or plant derived extracts and compounds, including metformin. Moreover, by using a CRISPR/Cas9 library, we will address the resistance of lung cancer cells to cisplatin, detecting possible new target genes related to cancer resistance by a genome-wide approach. Those genes related with cancer metabolism or the mTOR pathway will be preferentially chosen for validation and further exploration as targets for cancer therapy. The results derived from this project may contribute for a better understanding on how cancer cells control metabolism and how this control may be related to the response to natural compounds and chemotherapeutic drugs. (AU)

Scientific publications

(25)

(The scientific publications listed on this page originate from the Web of Science or SciELO databases. Their authors have cited FAPESP grant or fellowship project numbers awarded to Principal Investigators or Fellowship Recipients, whether or not they are among the authors. This information is collected automatically and retrieved directly from those bibliometric databases.)

SILVA MANCINI, MARIANA CAMARGO; SABOIA PONTE, LUIS GUSTAVO; ROCHA SILVA, CAYO HENRIQUE; FAGUNDES, ISABELLA; BETIM PAVAN, ISADORA CAROLINA; ROMEIRO, STEFHANI ANDRIOLI; SALVINO DA SILVA, LUIZ GUILHERME; MORELLI, ANA PAULA; ROSTAGNO, MAURICIO ARIEL; SIMABUCO, FERNANDO MOREIRA; et al. Beetroot and leaf extracts present protective effects against prostate cancer cells, inhibiting cell proliferation, migration, and growth signaling pathways. Phytotherapy Research, JUN 2021. (18/14818-9, 16/06457-0, 19/25582-9, 15/00311-1, 19/00607-9, 19/13848-4)

SIMABUCO, FERNANDO MOREIRA; TAMURA, RODRIGO ESAKI; BETIM PAVAN, ISADORA CAROLINA; MORALE, MIRIAN GALLIOTE; VENTURA, ARMANDO MORAIS. Molecular mechanisms and pharmacological interventions in the replication cycle of human coronaviruses. GENETICS AND MOLECULAR BIOLOGY, v. 44, n. 1, 1, 2021. (19/15619-2, 16/25139-0, 18/08391-2, 18/14818-9, 20/05346-6)

PINTO, ANA P.; MUNOZ, VITOR R.; DA ROCHA, ALISSON L.; ROVINA, RAFAEL L.; FERRARI, GUSTAVO D.; ALBERICI, LUCIANE C.; SIMABUCO, FERNANDO M.; TEIXEIRA, GIOVANA R.; PAULI, JOSE R.; DE MOURA, LEANDRO P.; et al. IL-6 deletion decreased REV-ERB alpha protein and influenced autophagy and mitochondrial markers in the skeletal muscle after acute exercise. FRONTIERS IN IMMUNOLOGY, v. 13, p. 13-pg., 2022-10-13. (21/06291-3, 21/08693-1, 19/11820-5, 17/12765-2, 19/21709-4, 21/08692-5, 20/13443-1, 18/14818-9)

ROMERO, STEFHANI ANDRIOLI; BETIM PAVAN, ISADORA CAROLINA; MORELLI, ANA PAULA; SILVA MANCINI, MARIANA CAMARGO; SALVINO DA SILVA, LUIZ GUILHERME; FAGUNDES, ISABELLA; ROCHA SILVA, CAYO HENRIQUE; SABOIA PONTE, LUIS GUSTAVO; ROSTAGNO, MAURICIO ARIEL; NEVES BEZERRA, ROSANGELA MARIA; et al. Anticancer effects of root and beet leaf extracts (Beta vulgaris L.) in cervical cancer cells (HeLa). Phytotherapy Research, v. 35, n. 11, SEP 2021. (18/14818-9, 16/06457-0, 19/25582-9, 15/00311-1, 19/00607-9, 19/13848-4)

SIMABUCO, FERNANDO MOREIRA; TAMURA, RODRIGO ESAKI; BETIM PAVAN, ISADORA CAROLINA; MORALE, MIRIAN GALLIOTE; VENTURA, ARMANDO MORAIS. Molecular mechanisms and pharmacological interventions in the replication cycle of human coronaviruses. GENETICS AND MOLECULAR BIOLOGY, v. 44, n. 1, p. 18-pg., 2021-01-01. (16/25139-0, 19/15619-2, 18/14818-9, 20/05346-6, 18/08391-2)

MORELLI, ANA PAULA; TORTELLI, THARCISIO CITRANGULO JR JR; BETIM PAVAN, ISADORA CAROLINA; SILVA, FERNANDO RIBACK; GRANATO, DANIELA CAMPOS; PERUCA, GUILHERME FRANCISCO; PAULETTI, BIANCA ALVES; DOMINGUES, ROMENIA RAMOS; NEVES BEZERRA, ROSANGELA MARIA; DE MOURA, LEANDRO PEREIRA; et al. Metformin impairs cisplatin resistance effects in A549 lung cancer cells through mTOR signaling and other metabolic pathways. International Journal of Oncology, v. 58, n. 6, JUN 2021. (19/00607-9, 15/22814-5, 17/04269-5, 15/16601-9, 18/14818-9, 16/06457-0, 12/13558-7)

CHAVES, FERNANDA MACHADO; BETIM PAVAN, ISADORA CAROLINA; SALVINO DA SILVA, LUIZ GUILHERME; DE FREITAS, LIDIA BROGLIO; ROSTAGNO, MAURICIO ARIEL; COSTA ANTUNES, ADRIANE ELISABETE; NEVES BEZERRA, ROSANGELA MARIA; SIMABUCO, FERNANDO MOREIRA. Pomegranate Juice and Peel Extracts are Able to Inhibit Proliferation, Migration and Colony Formation of Prostate Cancer Cell Lines and Modulate the Akt/mTOR/S6K Signaling Pathway. PLANT FOODS FOR HUMAN NUTRITION, v. 75, n. 1, p. 54-62, MAR 2020. (15/07299-7, 18/14818-9, 16/06457-0, 12/13558-7, 13/04304-4)

SALVINO DA SILVA, LUIZ GUILHERME; MORELLI, ANA PAULA; BETIM PAVAN, ISADORA CAROLINA; TAVARES, MARIANA ROSOLEN; PESTANA, NATHALIE FORTES; ROSTAGNO, MAURICIO ARIEL; SIMABUCO, FERNANDO MOREIRA; NEVES BEZERRA, ROSANGELA MARIA. Protective effects of beet (Beta vulgaris) leaves extract against oxidative stress in endothelial cells in vitro. Phytotherapy Research, v. 34, n. 6, JAN 2020. (16/06457-0, 12/13558-7, 13/04304-4, 18/14818-9)

DIAS, CLARISSA TAVARES; CURI, HAIDAR TAFNER; PAYOLLA, TANYARA BALIANI; LEMES, SIMONE FERREIRA; BETIM PAVAN, ISADORA CAROLINA; TORSONI, MARCIO ALBERTO; SIMABUCO, FERNANDO MOREIRA; LAMBERTUCCI, RAFAEL HERLING; DA SILVA, CRISTIANO MENDES. Maternal high-fat diet stimulates proinflammatory pathway and increases the expression of Tryptophan Hydroxylase 2 (TPH2) and brain-derived neurotrophic factor (BDNF) in adolescent mice hippocampus. NEUROCHEMISTRY INTERNATIONAL, v. 139, OCT 2020. (18/14818-9, 15/08441-1, 14/26146-4)

DE OLIVEIRA, ANDRESSA PERES; ISSAYAMA, LUIDY KAZUO; BETIM PAVAN, ISADORA CAROLINA; SILVA, FERNANDO RIBACK; MELO-HANCHUK, TALITA DINIZ; SIMABUCO, FERNANDO MOREIRA; KOBARG, JORG. Checking NEKs: Overcoming a Bottleneck in Human Diseases. Molecules, v. 25, n. 8, APR 2 2020. (14/15982-6, 18/14818-9, 17/03489-1)

MORELLI, ANA PAULA; TORTELLI JR, THARCISIO CITRANGULO; SILVA MANCINI, MARIANA CAMARGO; BETIM PAVAN, ISADORA CAROLINA; SALVINO SILVA, LUIZ GUILHERME; SEVERINO, MATHEUS BRANDEMARTE; GRANATO, DANIELA CAMPOS; PESTANA, NATHALIE FORTES; SABOIA PONTE, LUIS GUSTAVO; PERUCA, GUILHERME FRANCISCO; et al. TAT3 contributes to cisplatin resistance, modulating EMT markers, and the mTOR signaling in lung adenocarcinom. Neoplasia, v. 23, n. 10, p. 1048-1058, OCT 2021. (19/25582-9, 15/22814-5, 15/00311-1, 18/14818-9, 19/00607-9, 20/09527-5)

DE VICENTE, LARISSA G.; PINTO, ANA P.; MUNOZ, VITOR R.; ROVINA, RAFAEL L.; DA ROCHA, ALISSON L.; GASPAR, RAFAEL C.; DA SILVA, LILIAN E. C. M.; SIMABUCO, FERNANDO M.; FRANTZ, FABIANI G.; PAULI, JOSE R.; et al. Tlr4 participates in the responses of markers of apoptosis, inflammation, and ER stress to different acute exercise intensities in mice hearts. Life Sciences, v. 240, JAN 1 2020. (12/13558-7, 17/09038-1, 18/14818-9, 18/12519-4, 17/19869-8, 17/12765-2)

PONTE, LUIS GUSTAVO SABOIA; PAVAN, ISADORA CAROLINA BETIM; MANCINI, MARIANA CAMARGO SILVA; DA SILVA, LUIZ GUILHERME SALVINO; MORELLI, ANA PAULA; SEVERINO, MATHEUS BRANDEMARTE; BEZERRA, ROSANGELA MARIA NEVES; SIMABUCO, FERNANDO MOREIRA. The Hallmarks of Flavonoids in Cancer. Molecules, v. 26, n. 7, APR 2021. (18/08391-2, 19/00607-9, 19/25582-9, 18/14818-9)

SALVINO DA SILVA, LUIZ GUILHERME; MORELLI, ANA PAULA; BETIM PAVAN, ISADORA CAROLINA; TAVARES, MARIANA ROSOLEN; PESTANA, NATHALIE FORTES; ROSTAGNO, MAURICIO ARIEL; SIMABUCO, FERNANDO MOREIRA; NEVES BEZERRA, ROSANGELA MARIA. Protective effects of beet (Beta vulgaris) leaves extract against oxidative stress in endothelial cells in vitro. Phytotherapy Research, v. 34, n. 6, p. 12-pg., 2020-01-27. (16/06457-0, 13/04304-4, 12/13558-7, 18/14818-9)

SEVERINO, MATHEUS BRANDEMARTE; MORELLI, ANA PAULA; PAVAN, ISADORA CAROLINA BETIM; MANCINI, MARIANA CAMARGO SILVA; GOIS, MARIANA MARCELA; BORGES, RAFAEL JUNQUEIRA; BRAGA, RENATA ROSSETO; DA SILVA, LUIZ GUILHERME SALVINO; QUINTERO-RUIZ, NATHALIA; COSTA, MAIRA MAFTOUM; et al. A CRISPR-edited isoform of the AMPK kinase LKB1 improves the response to cisplatin in A549 lung cancer cells. Journal of Biological Chemistry, v. 301, n. 3, p. 21-pg., 2025-03-01. (18/14818-9, 20/13660-2)

PONTE, LUIS GUSTAVO SABOIA; MILANEZI, BEATRIZ TERUI; BARBOSA, IZABELLA BATISTA; PAVAN, ISADORA CAROLINA BETIM; MORELLI, ANA PAULA; SILVA MANCINI, MARIANA CAMARGO; DA SILVA, LUIZ GUILHERME SALVINO; FEITOR, JESSICA FREIRE; MORAIS, ALINE TEIXEIRA DO BRASIL; CARDOSO, DANIEL RODRIGUES; et al. Beet leaves after in vitro human gastrointestinal digestion present antioxidant capacity and protective effects in colorectal cancer cells. Food Research International, v. 221, p. 13-pg., 2025-12-01. (16/06457-0, 15/00311-1, 18/14818-9, 19/25582-9, 19/00607-9)

TAVARES, MARIANA ROSOLEN; LEMES, SIMONE FERREIRA; DE FANTE, THAIS; DE MIERA, CRISTINA SAENZ; BETIM PAVAN, ISADORA CAROLINA; NEVES BEZERRA, ROSANGELA MARIA; PRADA, PATRICIA OLIVEIRA; TORSONI, MARCIO ALBERTO; ELIAS, CAROL FUZETI; SIMABUCO, FERNANDO MOREIRA. Modulation of hypothalamic S6K1 and S6K2 alters feeding behavior and systemic glucose metabolism. Journal of Endocrinology, v. 244, n. 1, p. 71-82, JAN 2020. (12/13558-7, 13/22696-7, 18/14818-9, 18/07018-6, 15/24475-3, 16/06457-0)

PINTO, ANA P.; DA ROCHA, ALISSON L.; CABRERA, ELISA M. B.; MARAFON, BRUNO B.; KOHAMA, EIKE B.; ROVINA, RAFAEL L.; SIMABUCO, FERNANDO M.; BUENO JUNIOR, CARLOS R.; DE MOURA, LEANDRO P.; PAULI, JOSE R.; et al. Role of interleukin-6 in inhibiting hepatic autophagy markers in exercised mice. CYTOKINE, v. 130, JUN 2020. (17/09038-1, 18/14818-9, 18/12519-4, 17/19869-8, 17/12765-2, 19/10875-0)

TAMBORLIN, LETICIA; SUMERE, BEATRIZ ROCCHETTI; DE SOUZA, MARIANA CORREA; PESTANA, NATHALIE FORTES; AGUIAR, ANA CAROLINA; EBERLIN, MARCOS NOGUEIRA; SIMABUCO, FERNANDO MOREIRA; ROSTAGNO, MAURICIO ARIEL; LUCHESSI, AUGUSTO DUCATI. Characterization of pomegranate peel extracts obtained using different solvents and their effects on cell cycle and apoptosis in leukemia cells. FOOD SCIENCE & NUTRITION, v. 8, n. 10, AUG 2020. (18/17089-8, 15/18119-0, 19/06951-3, 10/18095-0, 18/14818-9, 17/21914-1, 13/04304-4)

MANCINI, MARIANA C. S.; MORELLI, ANA P.; SEVERINO, MATHEUS B.; PAVAN, ISADORA C. B.; ZAMBALDE, ERIKA P.; GOIS, MARIANA M.; DA SILVA, LUIZ G. S.; QUINTERO-RUIZ, NATHALIA; ROMEIRO, CAIO F.; DOS SANTOS JR, DANIEL F. G.; et al. Knockout of NRF2 triggers prostate cancer cells death through ROS modulation and sensitizes to cisplatin. Journal of Cellular Biochemistry, v. 123, n. 12, p. 14-pg., 2022-10-03. (20/09310-6, 20/09133-7, 16/06457-0, 20/13660-2, 20/09527-5, 15/00311-1, 20/08684-0, 18/14818-9, 19/00607-9, 19/25582-9, 19/25731-4)

SILVA MANCINI, MARIANA CAMARGO; SABOIA PONTE, LUIS GUSTAVO; ROCHA SILVA, CAYO HENRIQUE; FAGUNDES, ISABELLA; BETIM PAVAN, ISADORA CAROLINA; ROMEIRO, STEFHANI ANDRIOLI; SALVINO DA SILVA, LUIZ GUILHERME; MORELLI, ANA PAULA; ROSTAGNO, MAURICIO ARIEL; SIMABUCO, FERNANDO MOREIRA; et al. Beetroot and leaf extracts present protective effects against prostate cancer cells, inhibiting cell proliferation, migration, and growth signaling pathways. Phytotherapy Research, v. 35, n. 9, p. 5241-5258, SEP 2021. (19/13848-4, 18/14818-9, 16/06457-0, 15/00311-1, 19/25582-9, 19/00607-9)

NOGUEIRA, PEDRO A. S.; MOURA-ASSIS, ALEXANDRE; ZANESCO, ARIANE M.; BOMBASSARO, BRUNA; GALLO-FERRAZ, ANA L.; SIMOES, MARCELA R.; ENGEL, DAIANE F.; RAZOLLI, DANIELA S.; GASPAR, JOANA M.; DONATO JUNIOR, JOSE; et al. The orphan G protein-coupled receptor, GPR139, is expressed in the hypothalamus and is involved in the regulation of body mass, blood glucose, and insulin. Neuroscience Letters, v. 792, p. 8-pg., 2023-01-01. (20/01318-8, 13/07607-8, 18/14818-9)

CAETANO-SILVA, MARIA ELISA; SIMABUCO, FERNANDO MOREIRA; NEVES BEZERRA, ROSANGELA MARIA; DA SILVA, DANIELE CRISTINA; BARBOSA, EDER ALVES; MOREIRA, DANIEL CARNEIRO; BRAND, GUILHERME DOTTO; DE SOUZA DE ALMEIDA LEITE, JOSE ROBERTO; BERTOLDO PACHECO, MARIA TERESA. Isolation and Sequencing of Cu-, Fe-, and Zn-Binding Whey Peptides for Potential Neuroprotective Applications as Multitargeted Compounds. Journal of Agricultural and Food Chemistry, v. 68, n. 44, p. 12433-12443, NOV 4 2020. (18/14818-9, 17/16977-4, 16/06457-0)

MOURA-ASSIS, ALEXANDRE; NOGUEIRA, PEDRO A. S.; DE-LIMA-JUNIOR, JOSE C.; SIMABUCO, FERNANDO M.; GASPAR, JOANA M.; DONATO JR, JOSE; VELLOSO, LICIO A.. TLR4-interactor with leucine-rich repeats (TRIL) is involved in diet-induced hypothalamic inflammation. SCIENTIFIC REPORTS, v. 11, n. 1, SEP 9 2021. (18/14818-9, 17/02983-2, 13/07607-8)

PENA, FABIOLA DE LIMA; DE SOUZA, MARIANA CORREA; SANCHES, VITOR LACERDA; VIGANO, JULIANE; MANCINI, MARIANA CAMARGO SILVA; BRITO-OLIVEIRA, THAIS CARVALHO; DOS SANTOS, BARBARA GECIANA TOMAZ; DE QUEIROZ, GUILHERME HENRIQUE AGUIAR; TAMBORLIN, LETICIA; SIMABUCO, FERNANDO MOREIRA; et al. Phenolic profile, bioactivity and cytotoxicity of plant extracts from thyme, ginger, garlic, ground roasted coffee and coffee silverskin. INTERNATIONAL JOURNAL OF FOOD PROPERTIES, v. 28, n. 1, p. 18-pg., 2025-12-31. (23/03439-5, 18/14818-9, 19/13496-0)