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Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction
The mechanism of action of eprenetapopt (APR-246, PRIMA-1(MET)) as an anticancer agent remains unresolved, although the clinical development of eprenetapopt focuses on its reported mechanism of action as a mutant-p53 reactivator. Using unbiased approaches, this study demonstrates that eprenetapopt d...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for the Advancement of Science
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9473576/ https://www.ncbi.nlm.nih.gov/pubmed/36103522 http://dx.doi.org/10.1126/sciadv.abm9427 |
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author | Fujihara, Kenji M. Zhang, Bonnie Z. Jackson, Thomas D. Ogunkola, Moses O. Nijagal, Brunda Milne, Julia V. Sallman, David A. Ang, Ching-Seng Nikolic, Iva Kearney, Conor J. Hogg, Simon J. Cabalag, Carlos S. Sutton, Vivien R. Watt, Sally Fujihara, Asuka T. Trapani, Joseph A. Simpson, Kaylene J. Stojanovski, Diana Leimkühler, Silke Haupt, Sue Phillips, Wayne A. Clemons, Nicholas J. |
author_facet | Fujihara, Kenji M. Zhang, Bonnie Z. Jackson, Thomas D. Ogunkola, Moses O. Nijagal, Brunda Milne, Julia V. Sallman, David A. Ang, Ching-Seng Nikolic, Iva Kearney, Conor J. Hogg, Simon J. Cabalag, Carlos S. Sutton, Vivien R. Watt, Sally Fujihara, Asuka T. Trapani, Joseph A. Simpson, Kaylene J. Stojanovski, Diana Leimkühler, Silke Haupt, Sue Phillips, Wayne A. Clemons, Nicholas J. |
author_sort | Fujihara, Kenji M. |
collection | PubMed |
description | The mechanism of action of eprenetapopt (APR-246, PRIMA-1(MET)) as an anticancer agent remains unresolved, although the clinical development of eprenetapopt focuses on its reported mechanism of action as a mutant-p53 reactivator. Using unbiased approaches, this study demonstrates that eprenetapopt depletes cellular antioxidant glutathione levels by increasing its turnover, triggering a nonapoptotic, iron-dependent form of cell death known as ferroptosis. Deficiency in genes responsible for supplying cancer cells with the substrates for de novo glutathione synthesis (SLC7A11, SHMT2, and MTHFD1L), as well as the enzymes required to synthesize glutathione (GCLC and GCLM), augments the activity of eprenetapopt. Eprenetapopt also inhibits iron-sulfur cluster biogenesis by limiting the cysteine desulfurase activity of NFS1, which potentiates ferroptosis and may restrict cellular proliferation. The combination of eprenetapopt with dietary serine and glycine restriction synergizes to inhibit esophageal xenograft tumor growth. These findings reframe the canonical view of eprenetapopt from a mutant-p53 reactivator to a ferroptosis inducer. |
format | Online Article Text |
id | pubmed-9473576 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-94735762022-09-29 Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction Fujihara, Kenji M. Zhang, Bonnie Z. Jackson, Thomas D. Ogunkola, Moses O. Nijagal, Brunda Milne, Julia V. Sallman, David A. Ang, Ching-Seng Nikolic, Iva Kearney, Conor J. Hogg, Simon J. Cabalag, Carlos S. Sutton, Vivien R. Watt, Sally Fujihara, Asuka T. Trapani, Joseph A. Simpson, Kaylene J. Stojanovski, Diana Leimkühler, Silke Haupt, Sue Phillips, Wayne A. Clemons, Nicholas J. Sci Adv Biomedicine and Life Sciences The mechanism of action of eprenetapopt (APR-246, PRIMA-1(MET)) as an anticancer agent remains unresolved, although the clinical development of eprenetapopt focuses on its reported mechanism of action as a mutant-p53 reactivator. Using unbiased approaches, this study demonstrates that eprenetapopt depletes cellular antioxidant glutathione levels by increasing its turnover, triggering a nonapoptotic, iron-dependent form of cell death known as ferroptosis. Deficiency in genes responsible for supplying cancer cells with the substrates for de novo glutathione synthesis (SLC7A11, SHMT2, and MTHFD1L), as well as the enzymes required to synthesize glutathione (GCLC and GCLM), augments the activity of eprenetapopt. Eprenetapopt also inhibits iron-sulfur cluster biogenesis by limiting the cysteine desulfurase activity of NFS1, which potentiates ferroptosis and may restrict cellular proliferation. The combination of eprenetapopt with dietary serine and glycine restriction synergizes to inhibit esophageal xenograft tumor growth. These findings reframe the canonical view of eprenetapopt from a mutant-p53 reactivator to a ferroptosis inducer. American Association for the Advancement of Science 2022-09-14 /pmc/articles/PMC9473576/ /pubmed/36103522 http://dx.doi.org/10.1126/sciadv.abm9427 Text en Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution license (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Biomedicine and Life Sciences Fujihara, Kenji M. Zhang, Bonnie Z. Jackson, Thomas D. Ogunkola, Moses O. Nijagal, Brunda Milne, Julia V. Sallman, David A. Ang, Ching-Seng Nikolic, Iva Kearney, Conor J. Hogg, Simon J. Cabalag, Carlos S. Sutton, Vivien R. Watt, Sally Fujihara, Asuka T. Trapani, Joseph A. Simpson, Kaylene J. Stojanovski, Diana Leimkühler, Silke Haupt, Sue Phillips, Wayne A. Clemons, Nicholas J. Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction |
title | Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction |
title_full | Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction |
title_fullStr | Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction |
title_full_unstemmed | Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction |
title_short | Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction |
title_sort | eprenetapopt triggers ferroptosis, inhibits nfs1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction |
topic | Biomedicine and Life Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9473576/ https://www.ncbi.nlm.nih.gov/pubmed/36103522 http://dx.doi.org/10.1126/sciadv.abm9427 |
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