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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Vydané v:	Cell reports (Cambridge) Ročník 16; číslo 9; s. 2415 - 2427
Hlavní autori:	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
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States Elsevier Inc 30.08.2016 Cell Press Elsevier
Predmet:	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
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Shrnutí:	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.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Lead Contact Co-first author
ISSN:	2211-1247 2211-1247
DOI:	10.1016/j.celrep.2016.07.082