title: PTEN-regulated AKT/FoxO3a/Bim signaling contributes to Human cell glioblastoma apoptosis by platinum-maurocalcin conjugate.
abstract: A previous report has shown that a chimera between a platinum complexing agent (1) and the cell penetrating peptide maurocalcin, synthesized with D-amino acids, (DMCa), termed Pt-1-DMCa, is a highly successful anticancer compound that works by targeting the intracellular redox system in glioblastoma (GBM) cells. However, the detailed cellular mechanism whereby the conjugate specifically kills tumor cells remains unclear. Herein, we show that Pt-1-DMCa induces apoptosis in Human U87 GBM cells through reactive oxygen species (ROS)-dependent modulation of the PI3K/AKT/FoxO3a signalling pathway. First, we found that Pt-1-DMCa treatment of these cells induces inhibition of AKT and nuclear accumulation of FoxO3a thereby facilitating transcription of the target genes Bim and PTEN. Modulation of the AKT/FoxO3a/Bim signaling pathway by RNA interference confirms that these signaling events are critical for Pt-1-DMCa-induced apoptosis of U87 GBM cells. Furthermore, we reveal that FoxO3a-mediated up-regulation of PTEN exerts an additional inhibitory effect on the AKT survival pathway. Thus, our results demonstrate that the conjugate can induce ROS-dependent FoxO3a-mediated apoptosis in U87 cells through PTEN-mediated inhibition of the PI3K/AKT survival axis. Our results help elucidate the molecular mechanisms underlying Pt-1-DMCa-induced cell death in U87 GBM cells and support a theoretical basis for future applications of the MCa peptide.
authors.affiliation: Laboratoire de Biochimie, Unité de recherche UR 12ES08 "Signalisation Cellulaire et Pathologies" Faculté de Médecine de Monastir, 5019 Monastir, Tunisia.
authors.forename: Sonia
authors.initials: S
authors.lastname: Aroui
authors.affiliation: Inserm UMR1087/CNRS UMR6291, Institute of Thorax, LabEx Ion Channels, Science and Therapeutics, 44007 Nantes Cedex 1, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Dardevet
authors.affiliation: Institute Pasteur of Tunis, Laboratory of venins and therapeutic biomolecules, LR11IPT08,13, 1002, Tunis, Tunisia.
authors.forename: Feten
authors.initials: F
authors.lastname: Najlaoui
authors.affiliation: Laboratoire de Biochimie, Unité de recherche UR 12ES08 "Signalisation Cellulaire et Pathologies" Faculté de Médecine de Monastir, 5019 Monastir, Tunisia.
authors.forename: Meriem
authors.initials: M
authors.lastname: Kammoun
authors.affiliation: Laboratoire de Biochimie, Unité de recherche UR 12ES08 "Signalisation Cellulaire et Pathologies" Faculté de Médecine de Monastir, 5019 Monastir, Tunisia.
authors.forename: Amel
authors.initials: A
authors.lastname: Laajimi
authors.affiliation: Laboratory of Toxicology, Microbiology and Environmental Health, UR11ES70, Sciences Faculty of Sfax, University of Sfax BP1171, 3000 Sfax, Tunisia. Electronic address: fetoui.hamadi@gmail.com.
authors.forename: Hamadi
authors.initials: H
authors.lastname: Fetoui
authors.affiliation: Inserm UMR1087/CNRS UMR6291, Institute of Thorax, LabEx Ion Channels, Science and Therapeutics, 44007 Nantes Cedex 1, France; University of Nantes, 44007 Nantes, France; Smartox Biotechnology, 570 Rue de la Chimie, 38400 Saint-Martin d'Hères, France.
authors.forename: Michel
authors.initials: M
authors.lastname: De Waard
authors.affiliation: Laboratoire de Biochimie, Unité de recherche UR 12ES08 "Signalisation Cellulaire et Pathologies" Faculté de Médecine de Monastir, 5019 Monastir, Tunisia.
authors.forename: Abderraouf
authors.initials: A
authors.lastname: Kenani
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D000072224:Bcl-2-Like Protein 11 / Q000378:metabolism*; D045744:Cell Line, Tumor; D000071316:Forkhead Box Protein O3 / Q000378:metabolism*; D005909:Glioblastoma / Q000473:pathology*; D006801:Humans; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D010984:Platinum / Q000737:chemistry / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012604:Scorpion Venoms / Q000737:chemistry; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000072224:Bcl-2-Like Protein 11; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D012604:Scorpion Venoms; C406406:maurocalcine; D010984:Platinum; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human