title: PML at Mitochondria-Associated Membranes Is Critical for the Repression of Autophagy and Cancer Development.
abstract: The precise molecular mechanisms that coordinate apoptosis and autophagy in cancer remain to be determined. Here, we provide evidence that the tumor suppressor promyelocytic leukemia protein (PML) controls autophagosome formation at mitochondria-associated membranes (MAMs) and, thus, autophagy induction. Our in vitro and in vivo results demonstrate how PML functions as a repressor of autophagy. PML loss promotes tumor development, providing a growth advantage to tumor cells that use autophagy as a cell survival strategy during stress conditions. These findings demonstrate that autophagy inhibition could be paired with a chemotherapeutic agent to develop anticancer strategies for tumors that present PML downregulation.
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology and LTTA Center, University of Ferrara, Ferrara 44121, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: Missiroli
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology and LTTA Center, University of Ferrara, Ferrara 44121, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Bonora
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology and LTTA Center, University of Ferrara, Ferrara 44121, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Patergnani
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology and LTTA Center, University of Ferrara, Ferrara 44121, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Poletti
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology and LTTA Center, University of Ferrara, Ferrara 44121, Italy.
authors.forename: Mariasole
authors.initials: M
authors.lastname: Perrone
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Anatomic Pathology and Molecular Diagnostics, University of Ferrara, Ferrara 44121, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Gafà
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Anatomic Pathology and Molecular Diagnostics, University of Ferrara, Ferrara 44121, Italy.
authors.forename: Eros
authors.initials: E
authors.lastname: Magri
authors.affiliation: Experimental Imaging Center, San Raffaele Scientific Institute, Milan 20132, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Raimondi
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Anatomic Pathology and Molecular Diagnostics, University of Ferrara, Ferrara 44121, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Lanza
authors.affiliation: Experimental Imaging Center, San Raffaele Scientific Institute, Milan 20132, Italy; Department of Experimental Medicine, University of Genoa, Genoa 16132, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Tacchetti
authors.affiliation: Equipe 11 Labellisée par la Ligue contre le Cancer, Centre de Recherche des Cordeliers, Paris 75006, France; Cell Biology and Metabolomics platforms, Gustave Roussy Comprehensive Cancer Center, Villejuif 94800, France; INSERM, U1138, Paris 75006, France; Université Paris Descartes, Sorbonne Paris Cité, Paris 75006, France; Université Pierre et Marie Curie, Paris VI, Paris 75006, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris 75015, France; Karolinska Institute and Department of Women's and Children's Health, Karolinska University Hospital Q2:07, 17176 Stockholm, Sweden.
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.affiliation: Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, MA 02215, USA; Departments of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology and LTTA Center, University of Ferrara, Ferrara 44121, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Pinton
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology and LTTA Center, University of Ferrara, Ferrara 44121, Italy. Electronic address: grgclt@unife.it.
authors.forename: Carlotta
authors.initials: C
authors.lastname: Giorgi
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects / Q000235:genetics*; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D018450:Disease Progression; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology; D000071156:Promyelocytic Leukemia Protein / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D015514:Oncogene Proteins, Fusion; D010087:Oxides; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; D016159:Tumor Suppressor Protein p53; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; C070576:PML protein, human; C025946:3-methyladenine; D000225:Adenine; D000077237:Arsenic Trioxide; D002118:Calcium