title: Glycogen synthase kinase 3 regulates cell death and survival signaling in tumor cells under redox stress.
abstract: Targeting tumor-specific metabolic adaptations is a promising anticancer strategy when tumor defense mechanisms are restrained. Here, we show that redox-modulating drugs including the retinoid N-(4-hydroxyphenyl)retinamide (4HPR), the synthetic triterpenoid bardoxolone (2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid methyl ester), arsenic trioxide (As2O3), and phenylethyl isothiocyanate (PEITC), while affecting tumor cell viability, induce sustained Ser9 phosphorylation of the multifunctional kinase glycogen synthase kinase 3β (GSK3β). The antioxidant N-acetylcysteine decreased GSK3β phosphorylation and poly(ADP-ribose) polymerase cleavage induced by 4HPR, As2O3, and PEITC, implicating oxidative stress in these effects. GSK3β phosphorylation was associated with up-regulation of antioxidant enzymes, in particular heme oxygenase-1 (HO-1), and transient elevation of intracellular glutathione (GSH) in cells surviving acute stress, before occurrence of irreversible damage and death. Genetic inactivation of GSK3β or transfection with the non-phosphorylatable GSK3β-S9A mutant inhibited HO-1 induction under redox stress, while tumor cells resistant to 4HPR exhibited increased GSK3β phosphorylation, HO-1 expression, and GSH levels. The above-listed findings are consistent with a role for sustained GSK3β phosphorylation in a signaling network activating antioxidant effector mechanisms during oxidoreductive stress. These data underlie the importance of combination regimens of antitumor redox drugs with inhibitors of survival signaling to improve control of tumor development and progression and overcome chemoresistance.
authors.affiliation: IRCCS Azienda Ospedaliera Universitaria S. Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genova 16132, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Venè
authors.affiliation: IRCCS Azienda Ospedaliera Universitaria S. Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genova 16132, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Cardinali
authors.affiliation: IRCCS Azienda Ospedaliera Universitaria S. Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genova 16132, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Arena
authors.affiliation: IRCCS Azienda Ospedaliera Universitaria S. Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genova 16132, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Ferrari
authors.affiliation: IRCCS Azienda Ospedaliera Universitaria S. Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genova 16132, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Benelli
authors.affiliation: IRCCS Azienda Ospedaliera Universitaria S. Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genova 16132, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Minghelli
authors.affiliation: IRCCS Azienda Ospedaliera Universitaria S. Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genova 16132, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Poggi
authors.affiliation: Dipartimento di Biotecnologie e Scienze della Vita, Università degli Studi dell'Insubria, Varese 21100, Italy; Science and Technology Pole, IRCCS MultiMedica, Milan 20138, Italy.
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Noonan
authors.affiliation: Infrastruttura Ricerca-Statistica (I-RS), IRCCS Tecnologie Avanzate e Modelli Assistenziali in Oncologia, Arcispedale S. Maria Nuova, Reggio Emilia 42123, Italy. Electronic address: adriana.albini@asmn.re.it.
authors.forename: Adriana
authors.initials: A
authors.lastname: Albini
authors.affiliation: IRCCS Azienda Ospedaliera Universitaria S. Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genova 16132, Italy. Electronic address: francesca.tosetti@hsanmartino.it.
authors.forename: Francesca
authors.initials: F
authors.lastname: Tosetti
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics; D016923:Cell Death / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D020868:Gene Silencing; D005947:Glucose / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D014212:Tretinoin / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D014212:Tretinoin; C054441:retinamide; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D038362:Glycogen Synthase Kinase 3; D005978:Glutathione; D005947:Glucose