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Endogenous PP2A inhibitor CIP2A degradation by chaperone-mediated autophagy contributes to the antitumor effect of mitochondrial complex I inhibition

R. Cazzoli, F. Romeo, I. Pallavicini, S. Peri, M. Romanenghi, JA. Pérez-Valencia, E. Hagag, F. Ferrucci, M. Elgendy, O. Vittorio, S. Pece, M. Foiani, J. Westermarck, S. Minucci

. 2023 ; 42 (6) : 112616. [pub] 20230607

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc24001293

Combined inhibition of oxidative phosphorylation (OXPHOS) and glycolysis has been shown to activate a PP2A-dependent signaling pathway, leading to tumor cell death. Here, we analyze highly selective mitochondrial complex I or III inhibitors in vitro and in vivo to elucidate the molecular mechanisms leading to cell death following OXPHOS inhibition. We show that IACS-010759 treatment (complex I inhibitor) induces a reactive oxygen species (ROS)-dependent dissociation of CIP2A from PP2A, leading to its destabilization and degradation through chaperone-mediated autophagy. Mitochondrial complex III inhibition has analogous effects. We establish that activation of the PP2A holoenzyme containing B56δ regulatory subunit selectively mediates tumor cell death, while the arrest in proliferation that is observed upon IACS-010759 treatment does not depend on the PP2A-B56δ complex. These studies provide a molecular characterization of the events subsequent to the alteration of critical bioenergetic pathways and help to refine clinical studies aimed to exploit metabolic vulnerabilities of tumor cells.

Citace poskytuje Crossref.org

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$a Endogenous PP2A inhibitor CIP2A degradation by chaperone-mediated autophagy contributes to the antitumor effect of mitochondrial complex I inhibition / $c R. Cazzoli, F. Romeo, I. Pallavicini, S. Peri, M. Romanenghi, JA. Pérez-Valencia, E. Hagag, F. Ferrucci, M. Elgendy, O. Vittorio, S. Pece, M. Foiani, J. Westermarck, S. Minucci
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$a Combined inhibition of oxidative phosphorylation (OXPHOS) and glycolysis has been shown to activate a PP2A-dependent signaling pathway, leading to tumor cell death. Here, we analyze highly selective mitochondrial complex I or III inhibitors in vitro and in vivo to elucidate the molecular mechanisms leading to cell death following OXPHOS inhibition. We show that IACS-010759 treatment (complex I inhibitor) induces a reactive oxygen species (ROS)-dependent dissociation of CIP2A from PP2A, leading to its destabilization and degradation through chaperone-mediated autophagy. Mitochondrial complex III inhibition has analogous effects. We establish that activation of the PP2A holoenzyme containing B56δ regulatory subunit selectively mediates tumor cell death, while the arrest in proliferation that is observed upon IACS-010759 treatment does not depend on the PP2A-B56δ complex. These studies provide a molecular characterization of the events subsequent to the alteration of critical bioenergetic pathways and help to refine clinical studies aimed to exploit metabolic vulnerabilities of tumor cells.
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$a Romeo, Francesco $u Department of Experimental Oncology, IEO IRCCS, Istituto Europeo di Oncologia, Milan, Italy; Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
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$a Pallavicini, Isabella $u Department of Experimental Oncology, IEO IRCCS, Istituto Europeo di Oncologia, Milan, Italy
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$a Hagag, Eman $u Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany; Medical Clinic I, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
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$a Ferrucci, Filippo $u Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany; Medical Clinic I, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Mildred-Scheel Early Career Center, National Center for Tumor Diseases Dresden (NCT/UCC) University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
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$a Elgendy, Mohamed $u Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany; Medical Clinic I, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Mildred-Scheel Early Career Center, National Center for Tumor Diseases Dresden (NCT/UCC) University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany; Laboratory of Cancer Cell Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
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$a Vittorio, Orazio $u Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Randwick, NSW, Australia; School of Biomedical Sciences, UNSW Sydney, Randwick, NSW, Australia
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