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MicroRNA-126 induces autophagy by altering cell metabolism in malignant mesothelioma
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SYSNO ASEP 0465816 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title MicroRNA-126 induces autophagy by altering cell metabolism in malignant mesothelioma Author(s) Tomasetti, M. (IT)
Monaco, F. (IT)
Manzella, N. (IT)
Rohlena, Jakub (BTO-N) RID, ORCID
Rohlenová, Kateřina (BTO-N) ORCID, RID
Staffolani, S. (IT)
Gaetani, S. (IT)
Ciarapica, V. (IT)
Amati, M. (IT)
Bracci, M. (IT)
Valentino, M. (IT)
Goodwin, J. (IT)
Nguyen, M. (AU)
Truksa, Jaroslav (BTO-N) RID, ORCID
Sobol, Margaryta (UMG-J) RID
Hozák, Pavel (UMG-J) RID, ORCID
Dong, L.F. (AU)
Santarelli, L. (IT)
Neužil, Jiří (BTO-N) RIDNumber of authors 19 Source Title OncoTarget. - : Impact Journals LLC - ISSN 1949-2553
Roč. 7, č. 24 (2016), s. 36338-36352Number of pages 15 s. Language eng - English Country US - United States Keywords pyruvate-dehydrogenase kinase ; mir-126 ; angiogenesis ; tumor suppression Subject RIV EB - Genetics ; Molecular Biology R&D Projects GAP301/10/1937 GA ČR - Czech Science Foundation (CSF) LM2015062 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) TE01020118 GA TA ČR - Technology Agency of the Czech Republic (TA ČR) GA16-22823S GA ČR - Czech Science Foundation (CSF) ED1.1.00/02.0109 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Institutional support BTO-N - RVO:86652036 ; UMG-J - RVO:68378050 UT WOS 000377756800066 DOI 10.18632/oncotarget.8916 Annotation 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-1 alpha (HIF1 alpha)-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 HIF1 alpha 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. Workplace Institute of Biotechnology Contact Monika Kopřivová, Monika.Koprivova@ibt.cas.cz, Tel.: 325 873 700 Year of Publishing 2017
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