title: The energy blockers bromopyruvate and lonidamine lead GL15 glioblastoma cells to death by different p53-dependent routes.
abstract: The energy metabolism of tumor cells relies on aerobic glycolysis rather than mitochondrial oxidation. This difference between normal and cancer cells provides a biochemical basis for new therapeutic strategies aimed to block the energy power plants of cells. The effects produced by the energy blockers bromopyruvate (3BP) and lonidamine (LND) and the underlying biochemical mechanisms were investigated in GL15 glioblastoma cells. 3BP exerts early effects compared to LND, even though both drugs lead cells to death but by different routes. A dramatic decrease of ATP levels occurred after 1 hour treatment with 3BP, followed by cytochrome c and hexokinase II degradation, and by the decrease of both LC3I/LC3II ratio and p62, markers of an autophagic flux. In addition, Akt(Ser(473)) and p53(Ser(15)/Ser(315)) dephosphorylation occurred. In LND treatment, sustained ATP cellular levels were maintained up to 40 hours. The autophagic response of cells was overcome by apoptosis that was preceded by phosphatidylinositol disappearance and pAkt decrease. This last event favored p53 translocation to mitochondria triggering a p53-dependent apoptotic route, as observed at 48 and 72 hours. Adversely, in 3BP treatment, phospho-p53 dephosphorylation targeted p53 to MDM2-dependent proteolysis, thus channeling cells to irreversible autophagy.
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Davidescu
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Lara
authors.initials: L
authors.lastname: Macchioni
authors.affiliation: Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia, Italy.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Scaramozzino
authors.affiliation: Department of Medicine, University of Perugia, Perugia, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Cristina Marchetti
authors.affiliation: Department of Medicine, University of Perugia, Perugia, Italy.
authors.forename: Graziella
authors.initials: G
authors.lastname: Migliorati
authors.affiliation: IMM-CNR, Institute for Microelectronics and Microsystems, National Research Council, Lecce, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Vitale
authors.affiliation: Department of Basic Medical Sciences, Neuroscience and Sensory Organs, University of Bari "A. Moro", Bari, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Corcelli
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Roberti
authors.affiliation: Department of Chemistry, Biology and Biotechnology, University of Perugia, Perugia, Italy.
authors.forename: Emilia
authors.initials: E
authors.lastname: Castigli
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Lanfranco
authors.initials: L
authors.lastname: Corazzi
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D004734:Energy Metabolism / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D007191:Indazoles / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D011773:Pyruvates / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D007191:Indazoles; D011773:Pyruvates; D016159:Tumor Suppressor Protein p53; C017092:bromopyruvate; C016371:lonidamine