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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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2022
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.
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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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