Cargando…
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...
Autores principales: | , , , , , , , , , , |
---|---|
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 |
_version_ | 1783657295622701056 |
---|---|
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. |
format | Online Article Text |
id | pubmed-7915661 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT sanghvivirajr nrf2activationconfersresistancetoeif4ainhibitorsincancertherapy AT mohanprathibha nrf2activationconfersresistancetoeif4ainhibitorsincancertherapy AT singhkamini nrf2activationconfersresistancetoeif4ainhibitorsincancertherapy AT caolinlin nrf2activationconfersresistancetoeif4ainhibitorsincancertherapy AT berishajmarjan nrf2activationconfersresistancetoeif4ainhibitorsincancertherapy AT wolfeandrewl nrf2activationconfersresistancetoeif4ainhibitorsincancertherapy AT schatzjonathanh nrf2activationconfersresistancetoeif4ainhibitorsincancertherapy AT laillernathalie nrf2activationconfersresistancetoeif4ainhibitorsincancertherapy AT destanchinaelisa nrf2activationconfersresistancetoeif4ainhibitorsincancertherapy AT vialeagnes nrf2activationconfersresistancetoeif4ainhibitorsincancertherapy AT wendelhansguido nrf2activationconfersresistancetoeif4ainhibitorsincancertherapy |