Impairment of Autophagic Flux Participates in the Antitumor Effects of TAT-Cx43266-283 in Glioblastoma Stem Cells

Cancers

Sara G. Pelaz¹  Claudia Ollauri-Ibáñez¹  Concepción Lillo¹  Arantxa Tabernero¹ 

[1] Instituto de Neurociencias de Castilla y León (INCYL), Universidad de Salamanca, Calle Pintor Fernando Gallego 1, 37007 Salamanca, Spain;

关键词: glioblastoma;    autophagy;    connexin43;    c-Src;    glioblastoma stem cells;    cell-penetrating peptide;   

DOI  :  10.3390/cancers13174262

来源: DOAJ

【 摘 要 】

Autophagy is a physiological process by which various damaged or non-essential cytosolic components are recycled, contributing to cell survival under stress conditions. In cancer, autophagy can have antitumor or protumor effects depending on the developmental stage. Here, we use Western blotting, immunochemistry, and transmission electron microscopy to demonstrate that the antitumor peptide TAT-Cx43_266-283, a c-Src inhibitor, blocks autophagic flux in glioblastoma stem cells (GSCs) under basal and nutrient-deprived conditions. Upon nutrient deprivation, GSCs acquired a dormant-like phenotype that was disrupted by inhibition of autophagy with TAT-Cx43_266-283 or chloroquine (a classic autophagy inhibitor), leading to GSC death. Remarkably, dasatinib, a clinically available c-Src inhibitor, could not replicate TAT-Cx43_266-283 effect on dormant GSCs, revealing for the first time the possible involvement of pathways other than c-Src in TAT-Cx43_266-283 effect. TAT-Cx43_266-283 exerts an antitumor effect both in nutrient-complete and nutrient-deprived environments, which constitutes an advantage over chloroquine and dasatinib, whose effects depend on nutrient environment. Finally, our analysis of the levels of autophagy-related proteins in healthy and glioma donors suggests that autophagy is upregulated in glioblastoma, further supporting the interest in inhibiting this process in the most aggressive brain tumor and the potential use of TAT-Cx43_266-283 as a therapy for this type of cancer.

【 授权许可】

Unknown