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

Affiliations

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

PMID:  39446948  DOI: 10.1126/science.adk9167

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.

服用抗氧化剂维生素E补充剂的男性前列腺癌（PC）风险增加，但促氧化剂是否能够预防前列腺癌尚不明确。在这项研究中，我们发现一种促氧化的维生素K前体（亚硫酸氢钠，MSB）能够抑制小鼠前列腺癌的发展，通过氧化作用导致细胞死亡：MSB通过氧化关键的半胱氨酸拮抗重要的第三类磷脂酰肌醇（PI）3-激酶VPS34，这一过程涉及内涵体特性和分选，揭示了分选中的氧化还原检查点。在一个由MTM1缺失驱动的肌管肌病模型中，我们测试了MSB，结果显示，膳食MSB能改善肌肉组织学和功能，并延长寿命。这些发现加深了我们对促氧化剂选择性的理解，并表明明确其影响途径可能带来意想不到的治疗机会。

关键词：前列腺癌，VPS34，PIK3C3，佰乐博，佰乐博生物