Kenji M. Fujihara, Bonnie Z. Zhang, Thomas D. Jackson, Moses Ogunkola, Brunda Nijagal, Julia V. Milne, David A. Sallman, Ching-Seng Ang, Iva Nikolic, Conor J. Kearney, Simon J. Hogg, Carlos S. Cabalag, Vivien R. Sutton, Sally Watt, Asuka T. Fujihara, Joseph A. Trapani, Kaylene J. Simpson, Diana Stojanovski, Silke Leimkühler, Sue Haupt, Wayne A. Phillips, Nicholas J. Clemons
- The mechanism of action of eprenetapopt (APR-246, PRIMA-1MET) as an anticancer agent remains unresolved, al-though 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 limit-ing 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 findingsThe mechanism of action of eprenetapopt (APR-246, PRIMA-1MET) as an anticancer agent remains unresolved, al-though 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 limit-ing 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.…
MetadatenAuthor details: | Kenji M. FujiharaORCiD, Bonnie Z. Zhang, Thomas D. JacksonORCiD, Moses OgunkolaORCiDGND, Brunda NijagalORCiD, Julia V. MilneORCiD, David A. SallmanORCiD, Ching-Seng AngORCiD, Iva NikolicORCiD, Conor J. KearneyORCiD, Simon J. HoggORCiD, Carlos S. Cabalag, Vivien R. SuttonORCiD, Sally Watt, Asuka T. FujiharaORCiD, Joseph A. TrapaniORCiD, Kaylene J. SimpsonORCiD, Diana StojanovskiORCiD, Silke LeimkühlerORCiDGND, Sue HauptORCiD, Wayne A. PhillipsORCiD, Nicholas J. ClemonsORCiD |
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DOI: | https://doi.org/10.1126/sciadv.abm9427 |
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ISSN: | 2375-2548 |
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Pubmed ID: | https://pubmed.ncbi.nlm.nih.gov/36103522 |
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Title of parent work (English): | Science Advances |
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Publisher: | American Assoc. for the Advancement of Science |
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Place of publishing: | Washington |
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Publication type: | Article |
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Language: | English |
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Date of first publication: | 2022/09/14 |
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Publication year: | 2022 |
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Release date: | 2024/01/17 |
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Volume: | 8 |
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Issue: | 37 |
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Article number: | eabm9427 |
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Number of pages: | 13 |
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Funding institution: | National Health and Medical Research Council (NHMRC) [MCRF16002];; Department of Health and Human Services; Australian Research Training; Program (RTP) Scholarships; Alan & Kate Gibson Research Fellowship;; Victorian Centre for Functional Genomics - Australian Cancer Research; Foundation (ACRF); Australian Government's National Collaborative; Research Infrastructure Strategy (NCRIS) program; Peter MacCallum Cancer; Centre Foundation; University of Melbourne Research Collaborative; Infrastructure Program (MCRIP); [APP1120293] |
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Organizational units: | Mathematisch-Naturwissenschaftliche Fakultät / Institut für Biochemie und Biologie |
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DDC classification: | 5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie |
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Peer review: | Referiert |
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Publishing method: | Open Access / Gold Open-Access |
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License (German): | CC-BY - Namensnennung 4.0 International |
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