Dietary pro-oxidant therapy by a vitamin K precursor targets PI 3-kinase VPS34 function
Men taking antioxidant vitamin E supplements have increased prostate cancer (PC) risk. However, whether pro-oxidants protect from PC remained unclear. In this work, we show that a pro-oxidant vitamin K precursor [menadione sodium bisulfite (MSB)] suppresses PC progression in mice, killing cells through an oxidative cell death: MSB antagonizes the essential class III phosphatidylinositol (PI) 3-kinase VPS34-the regulator of endosome identity and sorting-through oxidation of key cysteines, pointing to a redox checkpoint in sorting. Testing MSB in a myotubular myopathy model that is driven by loss of <i>MTM1</i>-the phosphatase antagonist of VPS34-we show that dietary MSB improved muscle histology and function and extended life span. These findings enhance our understanding of pro-oxidant selectivity and show how definition of the pathways they impinge on can give rise to unexpected therapeutic opportunities.
Authors
- Michael Wigler (ORCID: https://orcid.org/0000-0003-4396-1971)
- Sarah D. Diermeier (ORCID: https://orcid.org/0000-0002-6120-2744)
- Mary R. Doherty (ORCID: https://orcid.org/0009-0003-3689-9628)
- Mikala Egeblad (ORCID: https://orcid.org/0000-0002-3371-1445)
- Charlotte Gineste (ORCID: https://orcid.org/0000-0001-8515-089X)
- Manojit Mosur Swamynathan (ORCID: https://orcid.org/0000-0003-1156-586X)
- Olaf Klingbeil (ORCID: https://orcid.org/0000-0001-7248-7506)
- Phyllis A. Gimotty (ORCID: https://orcid.org/0000-0002-3850-9799)
- Christopher R. Vakoc (ORCID: https://orcid.org/0000-0002-1158-7180)
- Ana S. Almeida (ORCID: https://orcid.org/0000-0001-8997-2639)
- Xiang Zhao (ORCID: https://orcid.org/0000-0003-3067-3970)
- Roger Williams (ORCID: https://orcid.org/0000-0001-7754-4207)
- James Hicks (ORCID: https://orcid.org/0000-0001-5353-4338)
- John E. Wilkinson (ORCID: https://orcid.org/0000-0001-9174-8556)
- Colleen R. Reczek (ORCID: https://orcid.org/0000-0002-9106-5912)
- Hilary Cox
- Keith D. Rivera (ORCID: https://orcid.org/0000-0003-2979-9576)
- Habeeb Alsudani (ORCID: https://orcid.org/0000-0002-0630-0800)
- Seung Tea Kim (ORCID: https://orcid.org/0000-0002-1004-9292)
- Navdeep S. Chandel (ORCID: https://orcid.org/0000-0001-7208-3886)
- Tali Herzka
- Kenneth Chang (ORCID: https://orcid.org/0000-0002-5833-3655)
- Jason W. Locasale (ORCID: https://orcid.org/0000-0002-7766-3502)
- Ram Prosad Chakrabarty (ORCID: https://orcid.org/0000-0002-5425-6306)
- Paolo Cifani (ORCID: https://orcid.org/0000-0002-4403-1277)
- Shan Kuang (ORCID: https://orcid.org/0000-0001-7316-0273)
- Darryl Pappin (ORCID: https://orcid.org/0000-0002-8981-8401)
- Grace Q. Gong (ORCID: https://orcid.org/0000-0002-7609-0466)
- Tobias Janowitz (ORCID: https://orcid.org/0000-0002-7820-3727)
- David A. Tuveson (ORCID: https://orcid.org/0000-0002-8017-2712)
- Dawid G. Nowak (ORCID: https://orcid.org/0000-0003-4910-8963)
- Diya Ghosh (ORCID: https://orcid.org/0000-0002-5271-5767)
- Grinu Mathew (ORCID: https://orcid.org/0000-0001-6115-6373)
- Kaitlin Watrud
- Jocelyn Laporte (ORCID: https://orcid.org/0000-0001-8256-5862)
- David J. Reiss (ORCID: https://orcid.org/0000-0001-5392-3034)
- Tse-Luen Wee (ORCID: https://orcid.org/0000-0002-4141-3157)
- Lloyd C. Trotman (ORCID: https://orcid.org/0000-0002-4794-1559)
- Francesca Minicozzi (ORCID: https://orcid.org/0009-0007-7910-3342)
- Juan Liu (ORCID: https://orcid.org/0000-0002-8693-4271)
- Youngkyu Park (ORCID: https://orcid.org/0000-0003-1169-6739)
- Jude Kendall
- E. H. C. Cheng
- Saulė Špokaitė (ORCID: https://orcid.org/0000-0001-9461-7957)
- Antoine N. Dessus
Institutions
- Northwestern University (US)
- Centre National de la Recherche Scientifique (FR)
- NewYork–Presbyterian Hospital (US)
- North Carolina State University (US)
- Johns Hopkins University (US)
- Inserm (FR)
- MRC Laboratory of Molecular Biology (GB)
- Cornell University (US)
- Cold Spring Harbor Laboratory (US)
- University of Michigan (US)
- Johns Hopkins Medicine (US)
- Institut de génétique et de biologie moléculaire et cellulaire (FR)
- Presbyterian Hospital (US)
- Convergent Science (United States) (US)
- APC Microbiome Institute (IE)
- Weill Cornell Medicine (US)
- University of Nebraska Medical Center (US)
- Stony Brook University (US)
- University of Pennsylvania (US)
- University of Otago (NZ)
Publication Details
- Journal
- Science
- Published
- 2024-10-24
- DOI
- https://doi.org/10.1126/science.adk9167
- Citations
- 37
- Primary Topic
- Retinoids in leukemia and cellular processes
- Type
- article
- Field-Weighted Citation Impact
- 8.65
Funders
- U.S. Department of Defense
- Amgen
- AstraZeneca
- FibroGen
- Cold Spring Harbor Laboratory
- Pershing Square Sohn Cancer Research Alliance
- Agios Pharmaceuticals
- Northwell Health
- National Institutes of Health
- Medical Research Council
- National Cancer Institute