ACx43 peptide inhibits metabolic plasticity in human glioma stem cells while sparing human neural stem cells and astrocytes

  1. S. G. Pelaz 11
  2. M. Jaraíz-Rodríguez 11
  3. A. Álvarez-Vázquez 11
  4. R. Talaverón 11
  5. L. García-Vicente 11
  6. R. Flores-Hernández 11
  7. M. Gómez de Cedrón 2
  8. M. Tabernero 2
  9. A. Ramírez De Molina 2
  10. C. Lillo 11
  11. J. M. Medina 11
  12. A. Tabernero 11
  1. 1 Universidad de Salamanca
    info

    Universidad de Salamanca

    Salamanca, España

    ROR https://ror.org/02f40zc51

  2. 2 Instituto IMDEA Alimentación
    info

    Instituto IMDEA Alimentación

    Madrid, España

    ROR https://ror.org/04g4ezh90

Actas:
XV European Meeting on Glial Cells in Health and Disease

ISSN: 0894-1491,  1098-1136

Año de publicación: 2021

Volumen: 69

Número: S1

Páginas: E559

Congreso: XV European Meeting on Glial Cells in Health and Disease

Tipo: Póster de Congreso

DOI: 10.1002/GLIA.24036 GOOGLE SCHOLAR lock_openAcceso abierto editor

Resumen

Glioblastoma is the most aggressive primary brain tumour and has a median survival of 16 months. Inhibition of c-Src activity in glioblastoma stem cells (GSCs, responsible for glioblastoma lethality) and primary glioblastoma cells by the cell-penetrating peptide TAT-Cx43266-283, based on Connexin43, reduces tumorigenicity and boosts survival in preclinical models (ref. 1). 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-Cx43266-283. The Connexin43 peptideTAT-Cx43266-283decreased glucose uptake in human GSCs and reduced oxidative phosphorylationwithout 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-Cx43266-283impaired metabolic plasticity, reducing GSC growth and survival under different nutrient environments. Finally, GSCs intracranially implanted with TAT-Cx43266-283showed decreased levels of important metabolic targets for cancer therapy, such as hexokinase-2 and GLUT-3. This is especially relevant since both HK-2 and GLUT-3 arenecessary for the development of glioblastoma in pre-clinical models and are associated with decreased overall survival in glioblastoma patients.The reduced ability of TAT-Cx43266-283treated GSCs to survive in metabolically challenging settings, such asthose with restricted nutrient availability or the ever-changing in vivo environment, allows us to conclude (ref. 2) that the advantageous metabolic plasticity of GSCs can be therapeutically exploited through the specific and cell-selective inhibition of c-Src by TAT-Cx43

Referencias bibliográficas

  • Jaraíz-Rodríguez M, et al. Connexin43 peptide, TAT-Cx43266-283, selectively targets glioma cells, impairs malignant growth and enhances survival in mouse models in vivo. Neuro Oncol 2019. doi: 10.1093/neuonc/noz243.
  • Pelaz, SG et al. Targeting metabolic plasticity in glioma stem cells in vitro and in vivo through specific inhibition of c-Src by TAT-Cx43266-283. Ebiomedicine 2020. doi: 10.1016/j.ebiom.2020.103134