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Caveolin-1-mediated sphingolipid oncometabolism underlies a metabolic vulnerability of prostate cancer

Author

Listed:
  • Jody Vykoukal

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Johannes F. Fahrmann

    (The University of Texas MD Anderson Cancer Center)

  • Justin R. Gregg

    (The University of Texas MD Anderson Cancer Center)

  • Zhe Tang

    (The University of Texas MD Anderson Cancer Center)

  • Spyridon Basourakos

    (The University of Texas MD Anderson Cancer Center)

  • Ehsan Irajizad

    (The University of Texas MD Anderson Cancer Center)

  • Sanghee Park

    (The University of Texas MD Anderson Cancer Center)

  • Guang Yang

    (The University of Texas MD Anderson Cancer Center)

  • Chad J. Creighton

    (The University of Texas MD Anderson Cancer Center
    Baylor College of Medicine, One Baylor Plaza)

  • Alia Fleury

    (The University of Texas MD Anderson Cancer Center)

  • Jeffrey Mayo

    (The University of Texas MD Anderson Cancer Center)

  • Adriana Paulucci-Holthauzen

    (The University of Texas MD Anderson Cancer Center)

  • Jennifer B. Dennison

    (The University of Texas MD Anderson Cancer Center)

  • Eunice Murage

    (The University of Texas MD Anderson Cancer Center)

  • Christine B. Peterson

    (The University of Texas MD Anderson Cancer Center)

  • John W. Davis

    (The University of Texas MD Anderson Cancer Center)

  • Jeri Kim

    (The University of Texas MD Anderson Cancer Center)

  • Samir Hanash

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center)

  • Timothy C. Thompson

    (The University of Texas MD Anderson Cancer Center)

Abstract

Plasma and tumor caveolin-1 (Cav-1) are linked with disease progression in prostate cancer. Here we report that metabolomic profiling of longitudinal plasmas from a prospective cohort of 491 active surveillance (AS) participants indicates prominent elevations in plasma sphingolipids in AS progressors that, together with plasma Cav-1, yield a prognostic signature for disease progression. Mechanistic studies of the underlying tumor supportive onco-metabolism reveal coordinated activities through which Cav-1 enables rewiring of cancer cell lipid metabolism towards a program of 1) exogenous sphingolipid scavenging independent of cholesterol, 2) increased cancer cell catabolism of sphingomyelins to ceramide derivatives and 3) altered ceramide metabolism that results in increased glycosphingolipid synthesis and efflux of Cav-1-sphingolipid particles containing mitochondrial proteins and lipids. We also demonstrate, using a prostate cancer syngeneic RM-9 mouse model and established cell lines, that this Cav-1-sphingolipid program evidences a metabolic vulnerability that is targetable to induce lethal mitophagy as an anti-tumor therapy.

Suggested Citation

  • Jody Vykoukal & Johannes F. Fahrmann & Justin R. Gregg & Zhe Tang & Spyridon Basourakos & Ehsan Irajizad & Sanghee Park & Guang Yang & Chad J. Creighton & Alia Fleury & Jeffrey Mayo & Adriana Paulucci, 2020. "Caveolin-1-mediated sphingolipid oncometabolism underlies a metabolic vulnerability of prostate cancer," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17645-z
    DOI: 10.1038/s41467-020-17645-z
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    Cited by:

    1. Liang Dong & Zhi Cao & Meixia Chen & Yang Liu & Xinran Ma & Yuting Lu & Yan Zhang & Kaichao Feng & Yang Zhang & Zhenzhen Meng & Qingming Yang & Yao Wang & Zhiqiang Wu & Weidong Han, 2024. "Inhibition of glycosphingolipid synthesis with eliglustat in combination with immune checkpoint inhibitors in advanced cancers: preclinical evidence and phase I clinical trial," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    2. Hanyu Rao & Changwei Liu & Aiting Wang & Chunxiao Ma & Yue Xu & Tianbao Ye & Wenqiong Su & Peijun Zhou & Wei-Qiang Gao & Li Li & Xianting Ding, 2023. "SETD2 deficiency accelerates sphingomyelin accumulation and promotes the development of renal cancer," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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