Myriam Catalano1,2, Giuseppina D’Alessandro1,2, Francesca Lepore3, Marco Corazzari3,4, Sara Caldarola3, Cristina Valacca5, Fiorella Faienza3, Vincenzo Esposito2, Cristina Limatola1,2, Francesco Cecconi3,5,6, Sabrina Di Bartolomeo3,5
1Istituto Pasteur-Fondazione Cenci Bolognetti and Department of Physiology and Pharmacology, Sapienza University of Rome, Italy
2Neuromed IRCCS, Via Atinese, Pozzilli, Italy
3Department of Biology, University of Rome Tor Vergata, Rome, Italy
4IRCCS ‘L. Spallanzani’, Rome, Italy
5Department of Neuroscience, IRCCS Santa Lucia Foundation, Rome, Italy
6Unit of Cell Stress and Survival, Danish Cancer Society Research Center, 2100 Copenhagen, Denmark
Tóm tắt
Cell migration and invasion are highly regulated processes involved in both physiological and pathological conditions. Here we show that autophagy modulation regulates the migration and invasion capabilities of glioblastoma (GBM) cells. We observed that during autophagy occurrence, obtained by nutrient deprivation or by pharmacological inhibition of the mTOR complexes, GBM migration and chemokine‐mediated invasion were both impaired. We also observed that SNAIL and SLUG, two master regulators of the epithelial–mesenchymal transition (EMT process), were down‐regulated upon autophagy stimulation and, as a consequence, we found a transcriptional and translational up‐regulation of N‐ and R‐cadherins. Conversely, in BECLIN 1‐silenced GBM cells, an increased migration capability and an up‐regulation of SNAIL and SLUG was observed, with a resulting decrease in N‐ and R‐cadherin mRNAs. ATG5 and ATG7 down‐regulation also resulted in an increased migration and invasion of GBM cells combined to an up‐regulation of the two EMT regulators. Finally, experiments performed in primary GBM cells from patients largely confirmed the results obtained in established cell cultures.Overall, our results indicate that autophagy modulation triggers a molecular switch from a mesenchymal phenotype to an epithelial‐like one in GBM cellular models. Since the aggressiveness and lethality of GBM is defined by local invasion and resistance to chemotherapy, we believe that our evidence provides a further rationale for including autophagy/mTOR‐based targets in the current therapeutical regimen of GBM patients.
