Oncotarget

Research Papers:

MicroRNA-126 induces autophagy by altering cell metabolism in malignant mesothelioma

Marco Tomasetti _, Federica Monaco, Nicola Manzella, Jakub Rohlena, Katerina Rohlenova, Sara Staffolani, Simona Gaetani, Veronica Ciarapica, Monica Amati, Massimo Bracci, Matteo Valentino, Jacob Goodwin, Maria Nguyen, Jaroslav Truksa, Margaryta Sobol, Pavel Hozak, Lan-Feng Dong, Lory Santarelli and Jiri Neuzil

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Oncotarget. 2016; 7:36338-36352. https://doi.org/10.18632/oncotarget.8916

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Abstract

Marco Tomasetti1, Federica Monaco1, Nicola Manzella1, Jakub Rohlena2, Katerina Rohlenova2, Sara Staffolani1, Simona Gaetani1, Veronica Ciarapica1, Monica Amati1, Massimo Bracci1, Matteo Valentino1, Jacob Goodwin3, Maria Nguyen3, Jaroslav Truksa2, Margaryta Sobol4, Pavel Hozak4, Lan-Feng Dong3, Lory Santarelli1, Jiri Neuzil2,3

1Department of Clinical and Molecular Science, Polytechnic University of Marche, 60020, Ancona, Italy

2Institute of Biotechnology, Czech Academy of Sciences, BIOCEV, Vestec-Prague West, 25242, Czech Republic

3School of Medical Science and Griffith Health Institute, Griffith University, Southport, Qld, 4222, Australia

4Institute of Molecular Genetics, Czech Academy of Sciences, Prague 4, 142 20, Czech Republic

Correspondence to:

Marco Tomasetti, e-mail: m.tomasetti@univpm.it

Jiri Neuzil, e-mail: j.neuzil@griffith.edu.au

Keywords: MIR126, malignant mesothelioma, autophagy, cell metabolism, tumor suppression

Received: October 23, 2015    Accepted: March 28, 2016    Published: April 22, 2016

ABSTRACT

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.


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