title: Autophagy takes place in mutated p53 neuroblastoma cells in response to hypoxia mimetic CoCl(2).
abstract: Solid tumors like neuroblastoma exhibit hypoxic areas, which can lead both to cell death or aggressiveness increase. Hypoxia is a known stress able to induce stabilization of p53, implicated in cell fate regulation. Recently, p53 appeared to be involved in autophagy in an opposite manner, depending on its location: when nuclear, it enhanced transcription of pro-autophagic genes whereas when cytoplasmic, it inhibited the autophagic process. Today, we used cobalt chloride, a hypoxia mimetic that inhibits proteasomal HIF-1 degradation and generates reactive oxygen species (ROS). We focused on CoCl2-induced cell death in a DNA-binding mutated p53 neuroblastoma cell line (SKNBE(2c)). An autophagic signaling was evidenced by an increase of Beclin-1, ATG 5-12, and LC3-II expression whereas the p53(mut) presence decreased with CoCl2 time exposure. Activation of the pathway seemed to protect cells from ROS production and, at least in part, from death. The autophagic inhibitors activated the apoptotic signaling and the death was enhanced. To delineate the eventual implication of the p53(mut) in the autophagic process in response to hypoxia, we monitored signaling in p53(WT)SHSY5Y cells, after either shRNA-p53 down-regulation or transcriptional activity inhibition by pifithrin alpha. We did not detect autophagy neither with p53(wt) nor when p53 was lacking whereas such a response was effective with a mutated or inactivated p53. To conclude, mutated p53 in neuroblastoma cells could be linked with the switch between apoptotic response and cell death by autophagy in response to hypoxic mimetic stress.
authors: EA 3842, Université de Limoges, Faculté de Médecine, 2, rue du Docteur Marcland, 87025 Limoges cedex, France.
authors: Thomas
authors: T
authors: Naves
authors: Soha
authors: S
authors: Jawhari
authors: Marie-Odile
authors: MO
authors: Jauberteau
authors: Marie-Hélène
authors: MH
authors: Ratinaud
authors: Mireille
authors: M
authors: Verdier
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D003035:Cobalt / Q000494:pharmacology*; D006801:Humans; D009154:Mutation; D009447:Neuroblastoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D017382:Reactive Oxygen Species; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D003035:Cobalt; C018021:cobaltous chloride