EIF4A inhibition prevents the onset of cytokine-induced muscle wasting by blocking the STAT3 and iNOS pathways

Zvi Cramer, Jason Sadek, Gabriela Galicia Vazquez, Sergio Di Marco, Arnim Pause, Jerry Pelletier, Imed Gallouzi

Research output: Contribution to journalArticle

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Abstract

Cachexia is a deadly muscle wasting syndrome that arises under conditions linked to chronic inflammation, such as cancer. Cytokines, including interferon γ (IFNγ), tumor necrosis factor α (TNFα) and interleukin-6 (IL-6), and their downstream effectors such as Signal Transducer and Activator of Transcription 3 (STAT3), have been shown to play a prominent role in muscle wasting. Previously, we demonstrated that Pateamine A (PatA), a compound that targets eukaryotic initiation factor 4A (eIF4A), could prevent muscle wasting by modulating the translation of the inducible Nitric Oxide Synthase (iNOS) mRNA. Here we show that hippuristanol, a compound that impedes eIF4A in a manner distinct from PatA, similarly inhibits the iNOS/NO pathway and cytokine-induced muscle wasting. Furthermore, we show that hippuristanol perturbs the activation of the STAT3 pathway and expression of STAT3-gene targets such as IL-6. The decreased activation of STAT3, which resulted from a decrease in STAT3 protein expression, was due to the inhibition of STAT3 translation as there were no changes in STAT3 mRNA levels. These effects are likely dependent on the inhibition of eIF4A activity since we observed similar results using PatA. Our results identify the inhibition of eIF4A-responsive transcripts, such as STAT3, as a viable approach to alleviate cachexia.

Original languageEnglish
Article number8414
JournalScientific Reports
Volume8
Issue number1
DOIs
Publication statusPublished - 1 Dec 2018

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STAT3 Transcription Factor
Nitric Oxide Synthase Type II
Eukaryotic Initiation Factor-4A
Cytokines
Muscles
Cachexia
Interleukin-6
STAT Transcription Factors
Wasting Syndrome
Messenger RNA
Interferons
Tumor Necrosis Factor-alpha
Inflammation

ASJC Scopus subject areas

  • General

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EIF4A inhibition prevents the onset of cytokine-induced muscle wasting by blocking the STAT3 and iNOS pathways. / Cramer, Zvi; Sadek, Jason; Vazquez, Gabriela Galicia; Di Marco, Sergio; Pause, Arnim; Pelletier, Jerry; Gallouzi, Imed.

In: Scientific Reports, Vol. 8, No. 1, 8414, 01.12.2018.

Research output: Contribution to journalArticle

Cramer, Zvi ; Sadek, Jason ; Vazquez, Gabriela Galicia ; Di Marco, Sergio ; Pause, Arnim ; Pelletier, Jerry ; Gallouzi, Imed. / EIF4A inhibition prevents the onset of cytokine-induced muscle wasting by blocking the STAT3 and iNOS pathways. In: Scientific Reports. 2018 ; Vol. 8, No. 1.
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