eIF4A inhibition prevents the onset of cytokine-induced muscle wasting by blocking the STAT3 and iNOS pathways
<div><p>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 an...
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| مؤلفون آخرون: | , , , , , |
| منشور في: |
2018
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| _version_ | 1864513513003679744 |
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| author | Zvi Cramer (10742876) |
| author2 | Jason Sadek (18629365) Gabriela Galicia Vazquez (18697006) Sergio Di Marco (387749) Arnim Pause (265677) Jerry Pelletier (28518) Imed-Eddine Gallouzi (387751) |
| author2_role | author author author author author author |
| author_facet | Zvi Cramer (10742876) Jason Sadek (18629365) Gabriela Galicia Vazquez (18697006) Sergio Di Marco (387749) Arnim Pause (265677) Jerry Pelletier (28518) Imed-Eddine Gallouzi (387751) |
| author_role | author |
| dc.creator.none.fl_str_mv | Zvi Cramer (10742876) Jason Sadek (18629365) Gabriela Galicia Vazquez (18697006) Sergio Di Marco (387749) Arnim Pause (265677) Jerry Pelletier (28518) Imed-Eddine Gallouzi (387751) |
| dc.date.none.fl_str_mv | 2018-05-30T03:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1038/s41598-018-26625-9 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/eIF4A_inhibition_prevents_the_onset_of_cytokine-induced_muscle_wasting_by_blocking_the_STAT3_and_iNOS_pathways/25930996 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biomedical and clinical sciences Clinical sciences Oncology and carcinogenesis Cachexia Muscle wasting syndrome Chronic inflammation Cancer Cytokines Interferon γ (IFNγ) |
| dc.title.none.fl_str_mv | eIF4A inhibition prevents the onset of cytokine-induced muscle wasting by blocking the STAT3 and iNOS pathways |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <div><p>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.</p><p> </p></div><h2>Other Information</h2> <p> Published in: Scientific Reports<br> License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1038/s41598-018-26625-9" target="_blank">https://dx.doi.org/10.1038/s41598-018-26625-9</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_4732d77859ff5f227bc0ae081982b8f2 |
| identifier_str_mv | 10.1038/s41598-018-26625-9 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/25930996 |
| publishDate | 2018 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | eIF4A inhibition prevents the onset of cytokine-induced muscle wasting by blocking the STAT3 and iNOS pathwaysZvi Cramer (10742876)Jason Sadek (18629365)Gabriela Galicia Vazquez (18697006)Sergio Di Marco (387749)Arnim Pause (265677)Jerry Pelletier (28518)Imed-Eddine Gallouzi (387751)Biomedical and clinical sciencesClinical sciencesOncology and carcinogenesisCachexiaMuscle wasting syndromeChronic inflammationCancerCytokinesInterferon γ (IFNγ)<div><p>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.</p><p> </p></div><h2>Other Information</h2> <p> Published in: Scientific Reports<br> License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1038/s41598-018-26625-9" target="_blank">https://dx.doi.org/10.1038/s41598-018-26625-9</a></p>2018-05-30T03:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1038/s41598-018-26625-9https://figshare.com/articles/journal_contribution/eIF4A_inhibition_prevents_the_onset_of_cytokine-induced_muscle_wasting_by_blocking_the_STAT3_and_iNOS_pathways/25930996CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/259309962018-05-30T03:00:00Z |
| spellingShingle | eIF4A inhibition prevents the onset of cytokine-induced muscle wasting by blocking the STAT3 and iNOS pathways Zvi Cramer (10742876) Biomedical and clinical sciences Clinical sciences Oncology and carcinogenesis Cachexia Muscle wasting syndrome Chronic inflammation Cancer Cytokines Interferon γ (IFNγ) |
| status_str | publishedVersion |
| title | eIF4A inhibition prevents the onset of cytokine-induced muscle wasting by blocking the STAT3 and iNOS pathways |
| title_full | eIF4A inhibition prevents the onset of cytokine-induced muscle wasting by blocking the STAT3 and iNOS pathways |
| title_fullStr | eIF4A inhibition prevents the onset of cytokine-induced muscle wasting by blocking the STAT3 and iNOS pathways |
| title_full_unstemmed | eIF4A inhibition prevents the onset of cytokine-induced muscle wasting by blocking the STAT3 and iNOS pathways |
| title_short | eIF4A inhibition prevents the onset of cytokine-induced muscle wasting by blocking the STAT3 and iNOS pathways |
| title_sort | eIF4A inhibition prevents the onset of cytokine-induced muscle wasting by blocking the STAT3 and iNOS pathways |
| topic | Biomedical and clinical sciences Clinical sciences Oncology and carcinogenesis Cachexia Muscle wasting syndrome Chronic inflammation Cancer Cytokines Interferon γ (IFNγ) |