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NRF2 Activation Confers Resistance to eIF4A Inhibitors in Cancer Therapy

SIMPLE SUMMARY: eIF4A-targeted translational inhibitors, such as silvestrol and its analogues, have emerged as strong anticancer therapies. Here, we tested the efficacy of eIF4A inhibition across a large and diverse panel of cancer cell lines and found B cell lymphomas to be the most sensitive group...

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Autores principales: Sanghvi, Viraj R., Mohan, Prathibha, Singh, Kamini, Cao, Linlin, Berishaj, Marjan, Wolfe, Andrew L., Schatz, Jonathan H., Lailler, Nathalie, de Stanchina, Elisa, Viale, Agnes, Wendel, Hans-Guido
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915661/
https://www.ncbi.nlm.nih.gov/pubmed/33562682
http://dx.doi.org/10.3390/cancers13040639
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author Sanghvi, Viraj R.
Mohan, Prathibha
Singh, Kamini
Cao, Linlin
Berishaj, Marjan
Wolfe, Andrew L.
Schatz, Jonathan H.
Lailler, Nathalie
de Stanchina, Elisa
Viale, Agnes
Wendel, Hans-Guido
author_facet Sanghvi, Viraj R.
Mohan, Prathibha
Singh, Kamini
Cao, Linlin
Berishaj, Marjan
Wolfe, Andrew L.
Schatz, Jonathan H.
Lailler, Nathalie
de Stanchina, Elisa
Viale, Agnes
Wendel, Hans-Guido
author_sort Sanghvi, Viraj R.
collection PubMed
description SIMPLE SUMMARY: eIF4A-targeted translational inhibitors, such as silvestrol and its analogues, have emerged as strong anticancer therapies. Here, we tested the efficacy of eIF4A inhibition across a large and diverse panel of cancer cell lines and found B cell lymphomas to be the most sensitive group. Moreover, we performed a genetic screen and identified NRF2 activation as a major mechanism of resistance to silvestrol and related eIF4A inhibitors. Mechanistically, NRF2 activation broadly increases protein synthesis, and this effect is more pronounced on specific mRNAs that require eIF4A for translation. Finally, blocking NRF2 function by preventing its deglycation restores silvestrol sensitivity in cells that harbor NRF2 activation. Overall, our findings indicate that eIF4A inhibitors are a feasible therapeutic option against lymphoma and other cancers and that NRF2 activation status may be an important predictor of their efficacy. ABSTRACT: Inhibition of the eIF4A RNA helicase with silvestrol and related compounds is emerging as a powerful anti-cancer strategy. We find that a synthetic silvestrol analogue (CR-1-31 B) has nanomolar activity across many cancer cell lines. It is especially active against aggressive MYC(+)/BCL2(+) B cell lymphomas and this likely reflects the eIF4A-dependent translation of both MYC and BCL2. We performed a genome-wide CRISPR/Cas9 screen and identified mechanisms of resistance to this new class of therapeutics. We identify three negative NRF2 regulators (KEAP1, CUL3, CAND1) whose inactivation is sufficient to cause CR1-31-B resistance. NRF2 is known to alter the oxidation state of translation factors and cause a broad increase in protein production. We find that NRF2 activation particularly increases the translation of some eIF4A-dependent mRNAs and restores MYC and BCL2 production. We know that NRF2 functions depend on removal of sugar adducts by the frutosamine-3-kinase (FN3K). Accordingly, loss of FN3K results in NRF2 hyper-glycation and inactivation and resensitizes cancer cells to eIF4A inhibition. Together, our findings implicate NRF2 in the translation of eIF4A-dependent mRNAs and point to FN3K inhibition as a new strategy to block NRF2 functions in cancer.
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spelling pubmed-79156612021-03-01 NRF2 Activation Confers Resistance to eIF4A Inhibitors in Cancer Therapy Sanghvi, Viraj R. Mohan, Prathibha Singh, Kamini Cao, Linlin Berishaj, Marjan Wolfe, Andrew L. Schatz, Jonathan H. Lailler, Nathalie de Stanchina, Elisa Viale, Agnes Wendel, Hans-Guido Cancers (Basel) Article SIMPLE SUMMARY: eIF4A-targeted translational inhibitors, such as silvestrol and its analogues, have emerged as strong anticancer therapies. Here, we tested the efficacy of eIF4A inhibition across a large and diverse panel of cancer cell lines and found B cell lymphomas to be the most sensitive group. Moreover, we performed a genetic screen and identified NRF2 activation as a major mechanism of resistance to silvestrol and related eIF4A inhibitors. Mechanistically, NRF2 activation broadly increases protein synthesis, and this effect is more pronounced on specific mRNAs that require eIF4A for translation. Finally, blocking NRF2 function by preventing its deglycation restores silvestrol sensitivity in cells that harbor NRF2 activation. Overall, our findings indicate that eIF4A inhibitors are a feasible therapeutic option against lymphoma and other cancers and that NRF2 activation status may be an important predictor of their efficacy. ABSTRACT: Inhibition of the eIF4A RNA helicase with silvestrol and related compounds is emerging as a powerful anti-cancer strategy. We find that a synthetic silvestrol analogue (CR-1-31 B) has nanomolar activity across many cancer cell lines. It is especially active against aggressive MYC(+)/BCL2(+) B cell lymphomas and this likely reflects the eIF4A-dependent translation of both MYC and BCL2. We performed a genome-wide CRISPR/Cas9 screen and identified mechanisms of resistance to this new class of therapeutics. We identify three negative NRF2 regulators (KEAP1, CUL3, CAND1) whose inactivation is sufficient to cause CR1-31-B resistance. NRF2 is known to alter the oxidation state of translation factors and cause a broad increase in protein production. We find that NRF2 activation particularly increases the translation of some eIF4A-dependent mRNAs and restores MYC and BCL2 production. We know that NRF2 functions depend on removal of sugar adducts by the frutosamine-3-kinase (FN3K). Accordingly, loss of FN3K results in NRF2 hyper-glycation and inactivation and resensitizes cancer cells to eIF4A inhibition. Together, our findings implicate NRF2 in the translation of eIF4A-dependent mRNAs and point to FN3K inhibition as a new strategy to block NRF2 functions in cancer. MDPI 2021-02-05 /pmc/articles/PMC7915661/ /pubmed/33562682 http://dx.doi.org/10.3390/cancers13040639 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Sanghvi, Viraj R.
Mohan, Prathibha
Singh, Kamini
Cao, Linlin
Berishaj, Marjan
Wolfe, Andrew L.
Schatz, Jonathan H.
Lailler, Nathalie
de Stanchina, Elisa
Viale, Agnes
Wendel, Hans-Guido
NRF2 Activation Confers Resistance to eIF4A Inhibitors in Cancer Therapy
title NRF2 Activation Confers Resistance to eIF4A Inhibitors in Cancer Therapy
title_full NRF2 Activation Confers Resistance to eIF4A Inhibitors in Cancer Therapy
title_fullStr NRF2 Activation Confers Resistance to eIF4A Inhibitors in Cancer Therapy
title_full_unstemmed NRF2 Activation Confers Resistance to eIF4A Inhibitors in Cancer Therapy
title_short NRF2 Activation Confers Resistance to eIF4A Inhibitors in Cancer Therapy
title_sort nrf2 activation confers resistance to eif4a inhibitors in cancer therapy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915661/
https://www.ncbi.nlm.nih.gov/pubmed/33562682
http://dx.doi.org/10.3390/cancers13040639
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