title: Chemotherapeutic induction of mitochondrial oxidative stress activates GSK-3α/β and Bax, leading to permeability transition pore opening and tumor cell death.
abstract: Survival of tumor cells is favored by mitochondrial changes that make death induction more difficult in a variety of stress conditions, such as exposure to chemotherapeutics. These changes are not fully characterized in tumor mitochondria, and include unbalance of the redox equilibrium, inhibition of permeability transition pore (PTP) opening through kinase signaling pathways and modulation of members of the Bcl-2 protein family. Here we show that a novel chemotherapeutic, the Gold(III)-dithiocarbamato complex AUL12, induces oxidative stress and tumor cell death both favoring PTP opening and activating the pro-apoptotic protein Bax of the Bcl-2 family. AUL12 inhibits the respiratory complex I and causes a rapid burst of mitochondrial superoxide levels, leading to activation of the mitochondrial fraction of GSK-3α/β and to the ensuing phosphorylation of the mitochondrial chaperone cyclophilin D, which in turn facilitates PTP opening. In addition, following AUL12 treatment, Bax interacts with active GSK-3α/β and translocates onto mitochondria, where it contributes to PTP induction and tumor cell death. These findings provide evidence that targeting the redox equilibrium maintained by mitochondria in tumor cells allows to hit crucial mechanisms that shield neoplasms from the toxicity of many anti-tumor strategies, and identify AUL12 as a promising chemotherapeutic compound.
authors.affiliation: Department of Molecular Medicine, University of Padova, Padova, Italy. federica.chiara@unipd.it
authors.forename: F
authors.initials: F
authors.lastname: Chiara
authors.forename: A
authors.initials: A
authors.lastname: Gambalunga
authors.forename: M
authors.initials: M
authors.lastname: Sciacovelli
authors.forename: A
authors.initials: A
authors.lastname: Nicolli
authors.forename: L
authors.initials: L
authors.lastname: Ronconi
authors.forename: D
authors.initials: D
authors.lastname: Fregona
authors.forename: P
authors.initials: P
authors.lastname: Bernardi
authors.forename: A
authors.initials: A
authors.lastname: Rasola
authors.forename: A
authors.initials: A
authors.lastname: Trevisan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016923:Cell Death; D002463:Cell Membrane Permeability / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D051028:bcl-2-Associated X Protein; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha