Author, as appears in the article.: McGrail, Kimberley; Granado-Martinez, Paula; Esteve-Puig, Rosaura; Garcia-Ortega, Sara; Ding, Yuxin; Sanchez-Redondo, Sara; Ferrer, Berta; Hernandez-Losa, Javier; Canals, Francesc; Manzano, Anna; Navarro-Sabate, Aura; Bartrons, Ramon; Yanes, Oscar; Perez-Alea, Mileidys; Munoz-Couselo, Eva; Garcia-Patos, Vicenc; Recio, Juan A
Department: Enginyeria Electrònica, Elèctrica i Automàtica
URV's Author/s: Yanes Torrado, Óscar
Keywords: Stress, physiological Sorafenib Proto-oncogene proteins b-raf Phosphofructokinase-2 Pfkfb2 protein, human Nras protein, human Mutation Mutant melanoma Membrane proteins Melanoma Humans Gtp phosphohydrolases Glycolysis Glucose Cell line, tumor Braf protein, human tumors survival raf phosphorylation mutations kinase glucose cancer 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase
Abstract: NRAS-mutated melanoma lacks a specific line of treatment. Metabolic reprogramming is considered a novel target to control cancer; however, NRAS-oncogene contribution to this cancer hallmark is mostly unknown. Here, we show that NRASQ61-mutated melanomas specific metabolic settings mediate cell sensitivity to sorafenib upon metabolic stress. Mechanistically, these cells are dependent on glucose metabolism, in which glucose deprivation promotes a switch from CRAF to BRAF signaling. This scenario contributes to cell survival and sustains glucose metabolism through BRAF-mediated phosphorylation of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-2/3 (PFKFB2/PFKFB3). In turn, this favors the allosteric activation of phosphofructokinase-1 (PFK1), generating a feedback loop that couples glycolytic flux and the RAS signaling pathway. An in vivo treatment of NRASQ61 mutant melanomas, including patient-derived xenografts, with 2-deoxy-D-glucose (2-DG) and sorafenib effectively inhibits tumor growth. Thus, we provide evidence for NRAS-oncogene contributions to metabolic rewiring and a proof-of-principle for the treatment of NRASQ61-mutated melanoma combining metabolic stress (glycolysis inhibitors) and previously approved drugs, such as sorafenib.© 2022. The Author(s).
Thematic Areas: Zootecnia / recursos pesqueiros Saúde coletiva Química Psicología Planejamento urbano e regional / demografia Physics and astronomy (miscellaneous) Physics and astronomy (all) Odontología Nutrição Multidisciplinary sciences Multidisciplinary Medicina veterinaria Medicina iii Medicina ii Medicina i Materiais Matemática / probabilidade e estatística Interdisciplinar Geociências General physics and astronomy General medicine General chemistry General biochemistry,genetics and molecular biology Farmacia Engenharias iv Educação física Ciências biológicas iii Ciências biológicas ii Ciências biológicas i Ciências ambientais Ciências agrárias i Ciência da computação Chemistry (miscellaneous) Chemistry (all) Biotecnología Biodiversidade Biochemistry, genetics and molecular biology (miscellaneous) Biochemistry, genetics and molecular biology (all) Astronomia / física Antropologia / arqueologia
licence for use: https://creativecommons.org/licenses/by/3.0/es/
Author's mail: oscar.yanes@urv.cat
Author identifier: 0000-0003-3695-7157
Record's date: 2024-10-12
Papper version: info:eu-repo/semantics/publishedVersion
Licence document URL: https://repositori.urv.cat/ca/proteccio-de-dades/
Papper original source: Nature Communications. 13 (1): 7113-7113
APA: McGrail, Kimberley; Granado-Martinez, Paula; Esteve-Puig, Rosaura; Garcia-Ortega, Sara; Ding, Yuxin; Sanchez-Redondo, Sara; Ferrer, Berta; Hernandez-L (2022). BRAF activation by metabolic stress promotes glycolysis sensitizing NRASQ61-mutated melanomas to targeted therapy. Nature Communications, 13(1), 7113-7113. DOI: 10.1038/s41467-022-34907-0
Entity: Universitat Rovira i Virgili
Journal publication year: 2022
Publication Type: Journal Publications
Repositori URV