PML at Mitochondria-Associated Membranes Is Critical for the Repression of Autophagy and Cancer Development

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 induc...

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Published in:Cell reports (Cambridge) Vol. 16; no. 9; pp. 2415 - 2427
Main Authors: Missiroli, Sonia, Bonora, Massimo, Patergnani, Simone, Poletti, Federica, Perrone, Mariasole, Gafà, Roberta, Magri, Eros, Raimondi, Andrea, Lanza, Giovanni, Tacchetti, Carlo, Kroemer, Guido, Pandolfi, Pier Paolo, Pinton, Paolo, Giorgi, Carlotta
Format: Journal Article
Language:English
Published: United States Elsevier Inc 30.08.2016
Cell Press
Elsevier
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ISSN:2211-1247, 2211-1247
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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. [Display omitted] •PML regulates autophagic processes from ER/MAM domains in a Ca2+-dependent manner•Localization of PML away from the MAMs is dependent on p53•Activation of autophagy by PML depletion promotes survival under stress conditions•Block of autophagy restores the activity of chemotherapy in PML-downregulated tumors Missiroli et al. demonstrate that the tumor suppressor promyelocytic leukemia protein (PML) works as a repressor of autophagy by controlling autophagosome formation at mitochondria-associated membranes (MAMs) in a p53-dependent manner. Together, their studies generate alternative anticancer strategies for tumors that present PML downregulation.
AbstractList 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. [Display omitted] •PML regulates autophagic processes from ER/MAM domains in a Ca2+-dependent manner•Localization of PML away from the MAMs is dependent on p53•Activation of autophagy by PML depletion promotes survival under stress conditions•Block of autophagy restores the activity of chemotherapy in PML-downregulated tumors Missiroli et al. demonstrate that the tumor suppressor promyelocytic leukemia protein (PML) works as a repressor of autophagy by controlling autophagosome formation at mitochondria-associated membranes (MAMs) in a p53-dependent manner. Together, their studies generate alternative anticancer strategies for tumors that present PML downregulation.
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.
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.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.
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. • PML regulates autophagic processes from ER/MAM domains in a Ca2+-dependent manner • Localization of PML away from the MAMs is dependent on p53 • Activation of autophagy by PML depletion promotes survival under stress conditions • Block of autophagy restores the activity of chemotherapy in PML-downregulated tumors Missiroli et al. demonstrate that the tumor suppressor promyelocytic leukemia protein (PML) works as a repressor of autophagy by controlling autophagosome formation at mitochondria-associated membranes (MAMs) in a p53-dependent manner. Together, their studies generate alternative anticancer strategies for tumors that present PML downregulation.
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.
Author Giorgi, Carlotta
Tacchetti, Carlo
Patergnani, Simone
Pinton, Paolo
Lanza, Giovanni
Raimondi, Andrea
Perrone, Mariasole
Bonora, Massimo
Poletti, Federica
Pandolfi, Pier Paolo
Gafà, Roberta
Missiroli, Sonia
Magri, Eros
Kroemer, Guido
AuthorAffiliation 2 Department of Morphology, Surgery and Experimental Medicine, Section of Anatomic Pathology and Molecular Diagnostics, University of Ferrara, Ferrara 44121, Italy
8 Université Paris Descartes, Sorbonne Paris Cité, Paris 75006, France
12 Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, MA 02215, USA
13 Departments of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
1 Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology and LTTA Center, University of Ferrara, Ferrara 44121, Italy
10 Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris 75015, France
3 Experimental Imaging Center, San Raffaele Scientific Institute, Milan 20132, Italy
6 Cell Biology and Metabolomics platforms, Gustave Roussy Comprehensive Cancer Center, Villejuif 94800, France
11 Karolinska Institute and Department of Women’s and Children’s Health, Karo
AuthorAffiliation_xml – name: 4 Department of Experimental Medicine, University of Genoa, Genoa 16132, Italy
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  surname: Patergnani
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  givenname: Giovanni
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  surname: Giorgi
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  organization: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology and LTTA Center, University of Ferrara, Ferrara 44121, Italy
BackLink https://www.ncbi.nlm.nih.gov/pubmed/27545895$$D View this record in MEDLINE/PubMed
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Snippet The precise molecular mechanisms that coordinate apoptosis and autophagy in cancer remain to be determined. Here, we provide evidence that the tumor suppressor...
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SubjectTerms Adenine - analogs & derivatives
Adenine - pharmacology
Animals
Antineoplastic Agents - pharmacology
Arsenic Trioxide
Arsenicals - pharmacology
Autophagy - drug effects
Autophagy - genetics
Calcium - metabolism
Cancer
Cell Line, Tumor
Disease Progression
Fibroblasts - cytology
Fibroblasts - drug effects
Fibroblasts - metabolism
Gene Expression Regulation, Neoplastic
Humans
Leukemia, Promyelocytic, Acute - genetics
Leukemia, Promyelocytic, Acute - metabolism
Leukemia, Promyelocytic, Acute - pathology
Life Sciences
Membrane Potential, Mitochondrial - drug effects
Mice
Mice, Knockout
Mitochondria - drug effects
Mitochondria - metabolism
Mitochondrial Membranes - drug effects
Mitochondrial Membranes - metabolism
Oncogene Proteins, Fusion - genetics
Oncogene Proteins, Fusion - metabolism
Oxides - pharmacology
Promyelocytic Leukemia Protein - deficiency
Promyelocytic Leukemia Protein - genetics
Promyelocytic Leukemia Protein - metabolism
Signal Transduction
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - metabolism
Xenograft Model Antitumor Assays
Title PML at Mitochondria-Associated Membranes Is Critical for the Repression of Autophagy and Cancer Development
URI https://dx.doi.org/10.1016/j.celrep.2016.07.082
https://www.ncbi.nlm.nih.gov/pubmed/27545895
https://www.proquest.com/docview/1816637101
https://hal.sorbonne-universite.fr/hal-01375400
https://pubmed.ncbi.nlm.nih.gov/PMC5011426
https://doaj.org/article/2d6efb2bd9824461bd46909dade1fae1
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