Počet záznamů: 1  

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

  1. 1.
    0465816 - BTÚ 2017 RIV US eng J - Článek v odborném periodiku
    Tomasetti, M. - Monaco, F. - Manzella, N. - Rohlena, Jakub - Rohlenová, Kateřina - Staffolani, S. - Gaetani, S. - Ciarapica, V. - Amati, M. - Bracci, M. - Valentino, M. - Goodwin, J. - Nguyen, M. - Truksa, Jaroslav - Sobol, Margaryta - Hozák, Pavel - Dong, L.F. - Santarelli, L. - Neužil, Jiří
    MicroRNA-126 induces autophagy by altering cell metabolism in malignant mesothelioma.
    OncoTarget. Roč. 7, č. 24 (2016), s. 36338-36352. ISSN 1949-2553
    Grant CEP: GA ČR(CZ) GAP301/10/1937; GA MŠMT LM2015062; GA TA ČR(CZ) TE01020118; GA ČR(CZ) GA16-22823S; GA MŠMT(CZ) ED1.1.00/02.0109
    Institucionální podpora: RVO:86652036 ; RVO:68378050
    Klíčová slova: pyruvate-dehydrogenase kinase * mir-126 * angiogenesis * tumor suppression
    Kód oboru RIV: EB - Genetika a molekulární biologie
    Impakt faktor: 5.168, rok: 2016

    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.
    Trvalý link: http://hdl.handle.net/11104/0264281

     
     
Počet záznamů: 1  

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