title: Autophagy and TrkC/NT-3 signaling joined forces boost the hypoxic glioblastoma cell survival.
abstract: Glioblastoma multiform (GBM), the most common and aggressive primary brain tumor, is characterized by a high degree of hypoxia and resistance to therapy because of its adaptation capacities, including autophagy and growth factors signaling. In this study, we show an efficient hypoxia-induced survival autophagy in four different GBM cell lines (U87MG, M059K, M059J and LN-18) and an activation of a particular neurotrophin signaling pathway. Indeed, the enhancement of both TrkC and NT-3 was followed by downstream p38MAPK phosphorylation, suggesting the occurrence of a survival autocrine loop. Autophagy inhibition increased the hypoxia-induced expression of TrkC and its phosphorylated form as well as the phosphorylation of p38, suggesting a complementary effect of the two processes, leading to cell survival. Alone, autophagy inhibition reduced cellular growth without inducing cell death. However, the double inhibition of autophagy and TrkC signaling was necessary to bring cells to death as shown by PARP cleavage, particularly important in hypoxia. Moreover, a very high expression of TrkC and NT-3 was found in tumor sections from GBM patients, highlighting the importance of neurotrophic signaling in GBM tumor cell survival. These data suggest that a combined treatment targeting these two pathways could be considered in order to induce the death of GBM cells.
authors.affiliation: EA 3842, Cellular Homeostasis and Pathologies, Limoges University, France.
authors.forename: Soha
authors.initials: S
authors.lastname: Jawhari
authors.affiliation: EA 3842, Cellular Homeostasis and Pathologies, Limoges University, France.
authors.forename: Barbara
authors.initials: B
authors.lastname: Bessette
authors.affiliation: EA 3842, Cellular Homeostasis and Pathologies, Limoges University, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Hombourger
authors.affiliation: EA 3842, Cellular Homeostasis and Pathologies, Limoges University, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Durand
authors.affiliation: EA 3842, Cellular Homeostasis and Pathologies, Limoges University, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Lacroix
authors.affiliation: EA 3842, Cellular Homeostasis and Pathologies, Limoges University, France.
authors.forename: François
authors.initials: F
authors.lastname: Labrousse
authors.affiliation: EA 3842, Cellular Homeostasis and Pathologies, Limoges University, France.
authors.forename: Marie-Odile
authors.initials: MO
authors.lastname: Jauberteau
authors.affiliation: EA 3842, Cellular Homeostasis and Pathologies, Limoges University, France.
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Ratinaud
authors.affiliation: EA 3842, Cellular Homeostasis and Pathologies, Limoges University, France.
authors.forename: Mireille
authors.initials: M
authors.lastname: Verdier
mesh_terms: D001343:Autophagy; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D000860:Hypoxia; D009414:Nerve Growth Factors / Q000378:metabolism*; D020933:Neurotrophin 3; D010766:Phosphorylation; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000378:metabolism; D020812:Receptor, trkC / Q000378:metabolism*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C000595808:NTF3 protein, human; D009414:Nerve Growth Factors; D020933:Neurotrophin 3; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D020812:Receptor, trkC; D048051:p38 Mitogen-Activated Protein Kinases