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

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F86652036%3A_____%2F16%3A00465816" target="_blank" >RIV/86652036:_____/16:00465816 - isvavai.cz</a>

Alternative codes found

RIV/68378050:_____/16:00465816

Result on the web

<a href="http://dx.doi.org/10.18632/oncotarget.8916" target="_blank" >http://dx.doi.org/10.18632/oncotarget.8916</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.18632/oncotarget.8916" target="_blank" >10.18632/oncotarget.8916</a>

Result language

angličtina

Original language name

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

Original language description

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.

Czech name

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Czech description

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Type

J_x - Unclassified - Peer-reviewed scientific article (Jimp, Jsc and Jost)

CEP classification

EB - Genetics and molecular biology

OECD FORD branch

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Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2016

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

OncoTarget

ISSN

1949-2553

e-ISSN

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Volume of the periodical

7

Issue of the periodical within the volume

24

Country of publishing house

US - UNITED STATES

Number of pages

15

Pages from-to

36338-36352

UT code for WoS article

000377756800066

EID of the result in the Scopus database

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