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.
| Original language | English (US) |
|---|---|
| Article number | eadk9167 |
| Journal | Science |
| Volume | 386 |
| Issue number | 6720 |
| DOIs | |
| State | Published - Oct 25 2024 |
Funding
L. Bianco, J. Coblentz, and M. Cahn for help with animal work; A. Brady and J. Cheong for supplying validated cancer cell lines from CSHL\u2019s tissue culture facility; and D. Tsang for help with the article. We thank Q. Gao, A. Nourjanova, D. Hoppe-Cahn, K. Milicich, L. Stecher, and K. Anne-Javier for help with histologic procedures and analysis. We thank J. Kuhl for the mouse anatomy artwork. Funding: This work was directly supported by grants from the National Cancer Institute (NCI), 1R01CA275128 (L.C.T.) and NCI 5R01CA137050 (L.C.T.); the Pershing Square Sohn Cancer Research Alliance (L.C.T.); funds from IC-MedTech (L.C.T.); the Department of Defense grant DoD W81XWH-22-10-358 (M.R.D.); the Simons Foundation, Life Sciences Founders Directed Giving-Research award no. 519054 (M.W.); a research collaboration grant between AstraZeneca UK Limited and the Medical Research Council, reference BSF2-10 (R.L.W.); and the Mark Foundation for Cancer Research 20-028-EDV (T.J.) and NCI R01CA193256 (J.W.L.). D.A.T. is a distinguished scholar and Director of the Lustgarten Foundation\u2013designated Laboratory of Pancreatic Cancer Research, supported by the Thompson Foundation, the Pershing Square Foundation, the Cold Spring Harbor Laboratory and Northwell Health Affiliation, the Northwell Health Tissue Donation Program, the Cold Spring Harbor Laboratory Association, and the National Institutes of Health (5P30CA45508, U01CA210240, R01CA229699, U01CA224013, 1R01CA188134, and 1R01CA190092). This research was furthermore supported by the Robertson Research Fund of Cold Spring Harbor Laboratory (L.C.T.), and it was done in collaboration with the Cold Spring Harbor Laboratory shared resources, which are supported by the National Institutes of Health (Cancer Center Support grant 5P30CA045508, D.A.T.) to support the flow cytometry, microscopy, functional genomics, tissue culture, MS, genome sequencing, gene targeting, animal husbandry, and histology analysis of this project. Author contributions: Conceptualization: M.M.S. and L.C.T. Experiments and data analysis: M.M.S., S.K., K.E.W., M.R.D., C.G., G.M., H.C., E.C., D.R., J.K., C.R.R., X.Z., T.H., S.K., O.K., J.Li., D.G.N., H.A., T.-L.W., Y.P., F.M., K.R., A.S.A., K.C., J.E.W., P.A.G., and S.D.D. SNS experiments: H.C., D.G.N., L.C.T., and J.K.; with help from A.S.A. and M.E.; under supervision of J.B.H., M.W., and L.C.T.; and analysis by M.M.S. and L.C.T., with help from J.K. RapidCaP animal generation and experiment execution: M.M.S., K.E.W., E.C., and T.H., with supervision and analysis by M.M.S., D.A.T., and L.C.T. CRISPR-Cas9 screens, concept, and execution: M.M.S., with help from K.C. and C.R.V., and data analysis by M.M.S. and L.C.T. MS and VPS34 biochemistry: J.Li., F.M., G.Q.G., R.P.C., S.\u0160., and A.N.D., supervised and analyzed by J.W.L., N.S.C., D.J.P., P.C., G.Q.G., R.L.W., M.M.S., and L.C.T. Myopathy analysis: C.G., D.R., and M.M.S., under supervision of T.J., L.C.T., and J.La. Data visualization: M.M.S. and L.C.T. Manuscript writing: G.Q.G., R.L.W., D.A.T., J.La., M.M.S., and L.C.T. Competing interests: R.L.W. received research funding from a grant involving AstraZeneca UK Limited. Unrelated to this work, M.E. has stock options in Agios Pharmaceuticals and was on the advisory board of Vividion Therapeutics. D.G.N. has patent WO2008110777 issued (Modulators of vegf splicing as pro-and antiangiogenic agents) with royalties paid and owns stock in Arvinas, Inc. D.A.T. receives stock options from Leap Therapeutics, Cygnal Therapeutics, Mestag Therapeutics, Xilis, and Dunad, all unrelated to the project. Also unrelated to this project, D.A.T. is a member of the scientific advisory boards for Leap Therapeutics, Cygnal Therapeutics, Mestag Therapeutics, Xilis, and Dunad; a scientific cofounder of Mestag Therapeutics; and has received research grant support from Fibrogen, Mestag, and ONO Therapeutics and has received consulting income from Amgen, all unrelated to this work. S.D.D. is founder and CSO of Amaroq Therapeutics Ltd. and RNAfold.AI Pty Ltd., T.J. consults for Flagship pioneering and LeapTx, and L.C.T. consults for Health Advances LLC, all unrelated to this work. Data and materials availability: All data are available in the manuscript and/or the supplementary materials. License information: Copyright \u00A9 2024 the authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original US government works. https://www.science.org/about/science-licenses-journal-article-reuse We acknowledge all the members of the Trotman laboratory, X. Jiang, V. Haucke, S. Gillessen-Sommer, A. Chabes, C. Tonelli, T. Oni, K. On, T. Miller, and S. Coutts for valuable advice and critical discussion of the data and manuscript. We thank G. DeNicola, V. Sanghvi, N. Tonks, M. Yamamoto, and W. X. Zong for reagents; P. Moody and C. Viola for help with FACS procedures; the Cold Spring Harbor Laboratory Animal Resources team, R. Rubino, L. Bianco, J. Coblentz, and M. Cahn for help with animal work; A. Brady and J. Cheong for supplying validated cancer cell lines from CSHL\u2019s tissue culture facility; and D. Tsang for help with the article. We thank Q. Gao, A. Nourjanova, D. Hoppe-Cahn, K. Milicich, L. Stecher, and K. Anne-Javier for help with histologic procedures and analysis. We thank J. Kuhl for the mouse anatomy artwork. This work was directly supported by grants from the National Cancer Institute (NCI), 1R01CA275128 (L.C.T.) and NCI 5R01CA137050 (L.C.T.); the Pershing Square Sohn Cancer Research Alliance (L.C.T.); funds from IC-MedTech (L.C.T.); the Department of Defense grant DoD W81XWH-22-10-358 (M.R.D.); the Simons Foundation, Life Sciences Founders Directed Giving-Research award no. 519054 (M.W.); a research collaboration grant between AstraZeneca UK Limited and the Medical Research Council, reference BSF2-10 (R.L.W.); and the Mark Foundation for Cancer Research 20-028-EDV (T.J.) and NCI R01CA193256 (J.W.L.). D.A.T. is a distinguished scholar and Director of the Lustgarten Foundation\u2013designated Laboratory of Pancreatic Cancer Research, supported by the Thompson Foundation, the Pershing Square Foundation, the Cold Spring Harbor Laboratory and Northwell Health Affiliation, the Northwell Health Tissue Donation Program, the Cold Spring Harbor Laboratory Association, and the National Institutes of Health (5P30CA45508, U01CA210240, R01CA229699, U01CA224013, 1R01CA188134, and 1R01CA190092). This research was furthermore supported by the Robertson Research Fund of Cold Spring Harbor Laboratory (L.C.T.), and it was done in collaboration with the Cold Spring Harbor Laboratory shared resources, which are supported by the National Institutes of Health (Cancer Center Support grant 5P30CA045508, D.A.T.) to support the flow cytometry, microscopy, functional genomics, tissue culture, MS, genome sequencing, gene targeting, animal husbandry, and histology analysis of this project.
ASJC Scopus subject areas
- General
