title: Autophagy induction impairs migration and invasion by reversing EMT in glioblastoma cells.
abstract: 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.
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti and Department of Physiology and Pharmacology, Sapienza University of Rome, Italy; Neuromed IRCCS, Via Atinese, Pozzilli, Italy.
authors.forename: Myriam
authors.initials: M
authors.lastname: Catalano
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti and Department of Physiology and Pharmacology, Sapienza University of Rome, Italy; Neuromed IRCCS, Via Atinese, Pozzilli, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: D'Alessandro
authors.affiliation: Department of Biology, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Lepore
authors.affiliation: Department of Biology, University of Rome Tor Vergata, Rome, Italy; IRCCS L. Spallanzani, Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Corazzari
authors.affiliation: Department of Biology, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Caldarola
authors.affiliation: Department of Neuroscience, IRCCS Santa Lucia Foundation, Rome, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Valacca
authors.affiliation: Department of Biology, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Fiorella
authors.initials: F
authors.lastname: Faienza
authors.affiliation: Neuromed IRCCS, Via Atinese, Pozzilli, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Esposito
authors.affiliation: Istituto Pasteur-Fondazione Cenci Bolognetti and Department of Physiology and Pharmacology, Sapienza University of Rome, Italy; Neuromed IRCCS, Via Atinese, Pozzilli, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Limatola
authors.affiliation: Department of Biology, University of Rome Tor Vergata, Rome, Italy; Department of Neuroscience, IRCCS Santa Lucia Foundation, Rome, Italy; Unit of Cell Stress and Survival, Danish Cancer Society Research Center, 2100 Copenhagen, Denmark.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cecconi
authors.affiliation: Department of Biology, University of Rome Tor Vergata, Rome, Italy; Department of Neuroscience, IRCCS Santa Lucia Foundation, Rome, Italy. Electronic address: sabrina.dibartolomeo@uniroma2.it.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Di Bartolomeo
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005909:Glioblastoma / Q000473:pathology*; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D009287:Naphthyridines / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C553294:1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one; D016895:Culture Media, Serum-Free; D007976:Leupeptins; D009287:Naphthyridines; D002738:Chloroquine; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde
keywords: Autophagy; Cell migration; EMT; Glioma