Targeting metabolic plasticity in glioma stem cells in vitro and in vivo through specific inhibition of c-Src by TAT-Cx43 266-283 .

Autor:	Pelaz SG; Instituto de Neurociencias de Castilla y León (INCYL), Universidad de Salamanca, Calle Pintor Fernando Gallego 1, Salamanca 37007, Spain; Departamento de Bioquímica y Biología Celular, Universidad de Salamanca, Edificio Departamental, Campus Miguel de Unamuno, Salamanca 37007, Spain; Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Virgen de la Vega, 10ª planta, Paseo de San Vicente, 58-182, Salamanca 37007, Spain., Jaraíz-Rodríguez M; Instituto de Neurociencias de Castilla y León (INCYL), Universidad de Salamanca, Calle Pintor Fernando Gallego 1, Salamanca 37007, Spain; Departamento de Bioquímica y Biología Celular, Universidad de Salamanca, Edificio Departamental, Campus Miguel de Unamuno, Salamanca 37007, Spain; Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Virgen de la Vega, 10ª planta, Paseo de San Vicente, 58-182, Salamanca 37007, Spain., Álvarez-Vázquez A; Instituto de Neurociencias de Castilla y León (INCYL), Universidad de Salamanca, Calle Pintor Fernando Gallego 1, Salamanca 37007, Spain; Departamento de Bioquímica y Biología Celular, Universidad de Salamanca, Edificio Departamental, Campus Miguel de Unamuno, Salamanca 37007, Spain; Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Virgen de la Vega, 10ª planta, Paseo de San Vicente, 58-182, Salamanca 37007, Spain., Talaverón R; Instituto de Neurociencias de Castilla y León (INCYL), Universidad de Salamanca, Calle Pintor Fernando Gallego 1, Salamanca 37007, Spain; Departamento de Bioquímica y Biología Celular, Universidad de Salamanca, Edificio Departamental, Campus Miguel de Unamuno, Salamanca 37007, Spain; Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Virgen de la Vega, 10ª planta, Paseo de San Vicente, 58-182, Salamanca 37007, Spain., García-Vicente L; Instituto de Neurociencias de Castilla y León (INCYL), Universidad de Salamanca, Calle Pintor Fernando Gallego 1, Salamanca 37007, Spain; Departamento de Bioquímica y Biología Celular, Universidad de Salamanca, Edificio Departamental, Campus Miguel de Unamuno, Salamanca 37007, Spain; Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Virgen de la Vega, 10ª planta, Paseo de San Vicente, 58-182, Salamanca 37007, Spain., Flores-Hernández R; Instituto de Neurociencias de Castilla y León (INCYL), Universidad de Salamanca, Calle Pintor Fernando Gallego 1, Salamanca 37007, Spain; Departamento de Bioquímica y Biología Celular, Universidad de Salamanca, Edificio Departamental, Campus Miguel de Unamuno, Salamanca 37007, Spain; Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Virgen de la Vega, 10ª planta, Paseo de San Vicente, 58-182, Salamanca 37007, Spain., Gómez de Cedrón M; Precision Nutrition and Cancer Program, Molecular Oncology and Nutritional Genomics of Cancer Group, IMDEA Food Institute, CEI UAM + CSIC, Carretera de Canto Blanco 8 E, Madrid 28049, Spain., Tabernero M; Precision Nutrition and Cancer Program, Molecular Oncology and Nutritional Genomics of Cancer Group, IMDEA Food Institute, CEI UAM + CSIC, Carretera de Canto Blanco 8 E, Madrid 28049, Spain., Ramírez de Molina A; Precision Nutrition and Cancer Program, Molecular Oncology and Nutritional Genomics of Cancer Group, IMDEA Food Institute, CEI UAM + CSIC, Carretera de Canto Blanco 8 E, Madrid 28049, Spain., Lillo C; Instituto de Neurociencias de Castilla y León (INCYL), Universidad de Salamanca, Calle Pintor Fernando Gallego 1, Salamanca 37007, Spain; Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Virgen de la Vega, 10ª planta, Paseo de San Vicente, 58-182, Salamanca 37007, Spain., Medina JM; Instituto de Neurociencias de Castilla y León (INCYL), Universidad de Salamanca, Calle Pintor Fernando Gallego 1, Salamanca 37007, Spain; Departamento de Bioquímica y Biología Celular, Universidad de Salamanca, Edificio Departamental, Campus Miguel de Unamuno, Salamanca 37007, Spain; Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Virgen de la Vega, 10ª planta, Paseo de San Vicente, 58-182, Salamanca 37007, Spain., Tabernero A; Instituto de Neurociencias de Castilla y León (INCYL), Universidad de Salamanca, Calle Pintor Fernando Gallego 1, Salamanca 37007, Spain; Departamento de Bioquímica y Biología Celular, Universidad de Salamanca, Edificio Departamental, Campus Miguel de Unamuno, Salamanca 37007, Spain; Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Virgen de la Vega, 10ª planta, Paseo de San Vicente, 58-182, Salamanca 37007, Spain. Electronic address: ataber@usal.es.
Jazyk:	angličtina
Zdroj:	EBioMedicine [EBioMedicine] 2020 Dec; Vol. 62, pp. 103134. Date of Electronic Publication: 2020 Nov 27.
DOI:	10.1016/j.ebiom.2020.103134
Abstrakt:	Background: Glioblastoma is the most aggressive primary brain tumour and has a very poor prognosis. Inhibition of c-Src activity in glioblastoma stem cells (GSCs, responsible for glioblastoma lethality) and primary glioblastoma cells by the peptide TAT-Cx43 266-283 reduces tumorigenicity, and boosts survival in preclinical models. Because c-Src can modulate cell metabolism and several reports revealed poor clinical efficacy of various antitumoral drugs due to metabolic rewiring in cancer cells, here we explored the inhibition of advantageous GSC metabolic plasticity by the c-Src inhibitor TAT-Cx43 266-283 . Methods: Metabolic impairment induced by the c-Src inhibitor TAT-Cx43 266-283 in vitro was assessed by fluorometry, western blotting, immunofluorescence, qPCR, enzyme activity assays, electron microscopy, Seahorse analysis, time-lapse imaging, siRNA, and MTT assays. Protein expression in tumours from a xenograft orthotopic glioblastoma mouse model was evaluated by immunofluorescence. Findings: TAT-Cx43 266-283 decreased glucose uptake in human GSCs and reduced oxidative phosphorylation without a compensatory increase in glycolysis, with no effect on brain cell metabolism, including rat neurons, human and rat astrocytes, and human neural stem cells. TAT-Cx43 266-283 impaired metabolic plasticity, reducing GSC growth and survival under different nutrient environments. Finally, GSCs intracranially implanted with TAT-Cx43 266-283 showed decreased levels of important metabolic targets for cancer therapy, such as hexokinase-2 and GLUT-3. Interpretation: The reduced ability of TAT-Cx43 266-283 -treated GSCs to survive in metabolically challenging settings, such as those with restricted nutrient availability or the ever-changing in vivo environment, allows us to conclude that the advantageous metabolic plasticity of GSCs can be therapeutically exploited through the specific and cell-selective inhibition of c-Src by TAT-Cx43 266-283 . Funding: Spanish Ministerio de Economía y Competitividad (FEDER BFU2015-70040-R and FEDER RTI2018-099873-B-I00), Fundación Ramón Areces. Fellowships from the Junta de Castilla y León, European Social Fund, Ministerio de Ciencia and Asociación Española Contra el Cáncer (AECC). Competing Interests: Declaration of Competing Interest The authors declare no competing interests. (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze:	MEDLINE
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