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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Bibliographic Details
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
Subjects:
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
ISSN:2211-1247, 2211-1247
Online Access:Get full text
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Summary: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.
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ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2016.07.082