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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Published inScience advances Vol. 8; no. 37; p. eabm9427
Main Authors 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.
Format Journal Article
LanguageEnglish
Published American Association for the Advancement of Science 16.09.2022
Subjects
Biomedicine and Life Sciences
Cancer
Immunology
Life Sciences
SciAdv r-articles
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Abstract 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. The mutant-p53 reactivator, eprenetapopt, kills tumor cells through inducing ferroptosis and not apoptosis.
AbstractList 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. The mutant-p53 reactivator, eprenetapopt, kills tumor cells through inducing ferroptosis and not apoptosis.
Author Fujihara, Asuka T.
Kearney, Conor J.
Ang, Ching-Seng
Cabalag, Carlos S.
Jackson, Thomas D.
Simpson, Kaylene J.
Haupt, Sue
Sutton, Vivien R.
Nijagal, Brunda
Watt, Sally
Stojanovski, Diana
Phillips, Wayne A.
Milne, Julia V.
Hogg, Simon J.
Clemons, Nicholas J.
Ogunkola, Moses O.
Leimkühler, Silke
Sallman, David A.
Trapani, Joseph A.
Fujihara, Kenji M.
Zhang, Bonnie Z.
Nikolic, Iva
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  surname: Fujihara
  fullname: Fujihara, Kenji M.
  organization: Gastrointestinal Cancer Program, Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia., Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia
– sequence: 2
  givenname: Bonnie Z.
  surname: Zhang
  fullname: Zhang, Bonnie Z.
  organization: Gastrointestinal Cancer Program, Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia., Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia
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  givenname: Thomas D.
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  surname: Jackson
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  organization: Department of Biochemistry and Pharmacology, The University of Melbourne, Parkville, Victoria, Australia., Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia
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  givenname: Moses O.
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  organization: Institute of Biochemistry and Biology Department for Molecular Enzymology, University of Potsdam, Potsdam, Germany
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  surname: Milne
  fullname: Milne, Julia V.
  organization: Gastrointestinal Cancer Program, Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia., Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia
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  givenname: David A.
  orcidid: 0000-0003-0504-8233
  surname: Sallman
  fullname: Sallman, David A.
  organization: Malignant Hematology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
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  givenname: Ching-Seng
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  surname: Ang
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  organization: Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, Victoria, Australia
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  surname: Nikolic
  fullname: Nikolic, Iva
  organization: Victorian Centre for Functional Genomics, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
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  givenname: Conor J.
  orcidid: 0000-0002-9891-5078
  surname: Kearney
  fullname: Kearney, Conor J.
  organization: Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia., Translational Hematology Program, Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
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  givenname: Simon J.
  orcidid: 0000-0002-3170-839X
  surname: Hogg
  fullname: Hogg, Simon J.
  organization: Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia., Translational Hematology Program, Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia., Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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  givenname: Carlos S.
  surname: Cabalag
  fullname: Cabalag, Carlos S.
  organization: Gastrointestinal Cancer Program, Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia., Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia., Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
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  givenname: Vivien R.
  orcidid: 0000-0002-3156-7355
  surname: Sutton
  fullname: Sutton, Vivien R.
  organization: Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia., Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
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  givenname: Sally
  surname: Watt
  fullname: Watt, Sally
  organization: Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia., Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
– sequence: 15
  givenname: Asuka T.
  orcidid: 0000-0001-5262-8690
  surname: Fujihara
  fullname: Fujihara, Asuka T.
  organization: Gastrointestinal Cancer Program, Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
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  givenname: Joseph A.
  orcidid: 0000-0003-0983-1532
  surname: Trapani
  fullname: Trapani, Joseph A.
  organization: Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia., Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
– sequence: 17
  givenname: Kaylene J.
  orcidid: 0000-0001-9136-1781
  surname: Simpson
  fullname: Simpson, Kaylene J.
  organization: Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia., Victorian Centre for Functional Genomics, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
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  givenname: Diana
  surname: Stojanovski
  fullname: Stojanovski, Diana
  organization: Department of Biochemistry and Pharmacology, The University of Melbourne, Parkville, Victoria, Australia
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  givenname: Silke
  orcidid: 0000-0003-3238-2122
  surname: Leimkühler
  fullname: Leimkühler, Silke
  organization: Institute of Biochemistry and Biology Department for Molecular Enzymology, University of Potsdam, Potsdam, Germany
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  givenname: Sue
  orcidid: 0000-0003-2484-1712
  surname: Haupt
  fullname: Haupt, Sue
  organization: Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia., Tumor Suppression and Cancer Sex Disparity Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
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  givenname: Wayne A.
  orcidid: 0000-0002-7961-638X
  surname: Phillips
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  organization: Gastrointestinal Cancer Program, Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia., Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia., Department of Surgery (St. Vincent’s Hospital), The University of Melbourne, Parkville, Victoria, Australia., Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
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  givenname: Nicholas J.
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  surname: Clemons
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  organization: Gastrointestinal Cancer Program, Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia., Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia
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Snippet The mechanism of action of eprenetapopt (APR-246, PRIMA-1 MET ) as an anticancer agent remains unresolved, although the clinical development of eprenetapopt...
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Cancer
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Title Eprenetapopt triggers ferroptosis, inhibits NFS1 cysteine desulfurase, and synergizes with serine and glycine dietary restriction
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https://pubmed.ncbi.nlm.nih.gov/PMC9473576
Volume 8
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