Dietary pro-oxidant therapy by a vitamin K precursor targets PI 3-kinase VPS34 function PMID: 39446948

Target-related Cytokines

2026-09-23

Dietary pro-oxidant therapy by a vitamin K precursor targets PI 3-kinase VPS34 function

Science. 2024 Oct 25;386(6720):eadk9167. doi: 10.1126/science.adk9167.

Manojit M Swamynathan ¹ ² , Shan Kuang ^# ¹ , Kaitlin E Watrud ^# ¹ , Mary R Doherty ^# ¹ , Charlotte Gineste ³ , Grinu Mathew ¹ ⁴ , Grace Q Gong ⁵ , Hilary Cox ¹ , Eileen Cheng ¹ , David Reiss ³ , Jude Kendall ¹ , Diya Ghosh ¹ , Colleen R Reczek ⁶ , Xiang Zhao ¹ , Tali Herzka ¹ , Saulė Špokaitė ⁵ , Antoine N Dessus ⁵ , Seung Tea Kim ¹ ² , Olaf Klingbeil ¹ , Juan Liu ⁷ , Dawid G Nowak ⁸ ⁹ ¹⁰ , Habeeb Alsudani ¹ , Tse-Luen Wee ¹ , Youngkyu Park ¹ , Francesca Minicozzi ¹ , Keith Rivera ¹ , Ana S Almeida ¹ ¹¹ , Kenneth Chang ¹ , Ram P Chakrabarty ⁶ , John E Wilkinson ¹² , Phyllis A Gimotty ¹³ , Sarah D Diermeier ¹⁴ , Mikala Egeblad ¹ ¹⁵ , Christopher R Vakoc ¹ , Jason W Locasale ⁷ , Navdeep S Chandel ⁶ , Tobias Janowitz ¹ , James B Hicks ¹ ¹⁶ , Michael Wigler ¹ , Darryl J Pappin ¹ , Roger L Williams ⁵ , Paolo Cifani ¹ , David A Tuveson ¹ , Jocelyn Laporte ³ , Lloyd C Trotman ¹

Affiliations

1. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11771, USA.
2. Graduate Program in Molecular and Cellular Biology, Stony Brook University, Stony Brook, NY 11794, USA.
3. Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR7104, Inserm U1258, Strasbourg University, Illkirch CEDEX 67404, France.
4. Eppley Institute, University of Nebraska Medical Center, Omaha, NE 68198, USA.
5. MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK.
6. Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
7. Department of Molecular and Structural Biochemistry, North Carolina State University, Raleigh, NC 27695, USA.
8. Department of Medicine, Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA.
9. Department of Pharmacology, Weill Cornell Medicine, New York, NY 10065, USA.
10. Division of Hematology and Medical Oncology, Department of Medicine, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA.
11. APC Microbiome Ireland and School of Microbiology, University College Cork, Cork T12 K8AF, Ireland.
12. Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
13. Perelman School of Medicine, Division of Biostatistics, University of Pennsylvania, Philadelphia, PA 19104, USA.
14. Department of Biochemistry, University of Otago, Dunedin 9016, New Zealand.
15. School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
16. Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA 90089, USA.
# Contributed equally.

Abstract

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 MTM1-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.