MicroRNA-126 induces autophagy by altering cell metabolism in malignant mesothelioma.
Autophagy favors both cell survival and cancer suppression, and increasing evidence reveals that microRNAs (MIRs) regulate autophagy. Previously we reported that MIR126 is downregulated in malignant mesothelioma (MM). Therefore, we investigated the role of MIR126 in the regulation of cell metabolism and autophagy in MM models. We report that MIR126 induces autophagic flux in MM cells by downregulating insulin receptor substrate-1 (IRS1) and disrupting the IRS1 signaling pathway. This was specific to MM cells, and was not observed in non-malignant cells of mesothelial origin or in MM cells expressing MIR126-insensitive IRS1 transcript. The MIR126 effect on autophagy in MM cells was recapitulated by IRS1 silencing, and antagonized by IRS1 overexpression or antisense MIR126 treatment. The MIR126-induced loss of IRS1 suppressed glucose uptake, leading to energy deprivation and AMPK-dependent phosphorylation of ULK1. In addition, MIR126 stimulated lipid droplet accumulation in a hypoxia-inducible factor-1α (HIF1α)-dependent manner. MIR126 also reduced pyruvate dehydrogenase kinase (PDK) and acetyl-CoA-citrate lyase (ACL) expression, leading to the accumulation of cytosolic citrate and paradoxical inhibition of pyruvate dehydrogenase (PDH) activity. Simultaneous pharmacological and genetic intervention with PDK and ACL activity phenocopied the effects of MIR126. This suggests that in MM MIR126 initiates a metabolic program leading to high autophagic flux and HIF1α stabilization, incompatible with tumor progression of MM. Consistently, MIR126-expressing MM cells injected into immunocompromised mice failed to progress beyond the initial stage of tumor formation, showing that increased autophagy has a protective role in MM.
Department of Clinical and Molecular Science, Polytechnic University of Marche, 60020, Ancona, Italy.
Marco
M
Tomasetti
Department of Clinical and Molecular Science, Polytechnic University of Marche, 60020, Ancona, Italy.
Federica
F
Monaco
Department of Clinical and Molecular Science, Polytechnic University of Marche, 60020, Ancona, Italy.
Nicola
N
Manzella
Institute of Biotechnology, Czech Academy of Sciences, BIOCEV, Vestec-Prague West, 25242, Czech Republic.
Jakub
J
Rohlena
Institute of Biotechnology, Czech Academy of Sciences, BIOCEV, Vestec-Prague West, 25242, Czech Republic.
Katerina
K
Rohlenova
Department of Clinical and Molecular Science, Polytechnic University of Marche, 60020, Ancona, Italy.
Sara
S
Staffolani
Department of Clinical and Molecular Science, Polytechnic University of Marche, 60020, Ancona, Italy.
Simona
S
Gaetani
Department of Clinical and Molecular Science, Polytechnic University of Marche, 60020, Ancona, Italy.
Veronica
V
Ciarapica
Department of Clinical and Molecular Science, Polytechnic University of Marche, 60020, Ancona, Italy.
Monica
M
Amati
Department of Clinical and Molecular Science, Polytechnic University of Marche, 60020, Ancona, Italy.
Massimo
M
Bracci
Department of Clinical and Molecular Science, Polytechnic University of Marche, 60020, Ancona, Italy.
Matteo
M
Valentino
School of Medical Science and Griffith Health Institute, Griffith University, Southport, Qld, 4222, Australia.
Jacob
J
Goodwin
School of Medical Science and Griffith Health Institute, Griffith University, Southport, Qld, 4222, Australia.
Maria
M
Nguyen
Institute of Biotechnology, Czech Academy of Sciences, BIOCEV, Vestec-Prague West, 25242, Czech Republic.
Jaroslav
J
Truksa
Institute of Molecular Genetics, Czech Academy of Sciences, Prague 4, 142 20, Czech Republic.
Margaryta
M
Sobol
Institute of Molecular Genetics, Czech Academy of Sciences, Prague 4, 142 20, Czech Republic.
Pavel
P
Hozak
School of Medical Science and Griffith Health Institute, Griffith University, Southport, Qld, 4222, Australia.
Lan-Feng
LF
Dong
Department of Clinical and Molecular Science, Polytechnic University of Marche, 60020, Ancona, Italy.
Lory
L
Santarelli
Institute of Biotechnology, Czech Academy of Sciences, BIOCEV, Vestec-Prague West, 25242, Czech Republic.|School of Medical Science and Griffith Health Institute, Griffith University, Southport, Qld, 4222, Australia.
Jiri
J
Neuzil
D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D001343:Autophagy / Q000235:genetics*; D001483:Base Sequence; D002460:Cell Line; D045744:Cell Line, Tumor; D015536:Down-Regulation; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics* / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008654:Mesothelioma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D012689:Sequence Homology, Nucleic Acid; D015398:Signal Transduction / Q000235:genetics; D014183:Transplantation, Heterologous
D020413:3' Untranslated Regions; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; C527111:MIRN126 microRNA, human; D035683:MicroRNAs
MIR126; autophagy; cell metabolism; malignant mesothelioma; tumor suppression